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Progress in Neurobiology 63 (2001) 613 635

www.elsevier.com/locate/pneurobio

Modulation of spontaneous quantal release of neurotransmitters in


the hippocampus
Alexandre Bouron *
CNRS UMR 5091, Institut Francois Magendie, Rue Camille Saint-Saens, 33077 Bordeaux Cedex, France

Received 9 June 2000

Abstract

Presynaptic action potentials trigger the exocytosis of neurotransmitters. However, even in the absence of depolarisation-depen-
dent Ca2 + entry nearby release sites, spontaneous vesicular release still occurs. Even though this happens at low rate, such
spontaneous release may play a trophic role in maintaining the shape of dendritic structures. Like evoked responses, action
potential-independent release is subject to modulation. This review describes some of the regulatory factors that rapidly and
presynaptically regulate the ongoing Ca2 + -independent release of neurotransmitters in the hippocampus. For instance, the
electrical activity of the nerve ending, neurotransmitters, hypertonic solutions, neurotoxins, polycations, neurotrophic factors,
immunoglobulins, cyclothiazide and psychotropic drugs can all modify the rate of spontaneous release. This can be achieved
through various mechanisms that can be Ca2 + -dependent or Ca2 + -independent, protein kinase-dependent or independent. Since
action potential-independent release contributes to the maintenance of dendritic structures, neuromodulators are likely to
influence the density and/or length of dendritic spines, which in turn may modulate information processing in the central nervous
system (CNS). 2001 Elsevier Science Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614

2. Presynaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615

3. Modulation of spontaneous quantal release in the hippocampus. . . . . . . . . . . . . . . . . . . 615


3.1. Electrical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
3.2. Cations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

Abbre6iations: 1S,3R-ACPD, 1S,3R-1-aminocyclopentane-1.3-dicarboxylic acid; a-LTx, alpha-latrotoxin; AMPA, a-amino-3-hydroxy-5-methyl-


4-isoxazolepropionic acid; APV, 2-amino-5-phosphonovalerate; ATP, adenosine 5-trisphosphate; BDNF, brain-derived neurotrophic factor;
BoNT, botulinum neurotoxin; CNS, central nervous system; DAG, diacylglycerol; EGTA, ethylene glycol-bis(b amino-ethyl ether)-N,N,N,N-te-
traacetic acid; GABA, g-aminobutyric acid; GAP-43, FI, B-50 or neuromodulin; G protein, guanine nucleotide binding protein; IgG,
immunoglobulin; IP3, inositol 1,4,5-trisphosphate; LTD, long-term depression; LTP, long-term potentiation; mEPSC, miniature excitatory
postsynaptic current; mIPSC, miniature inhibitory postsynaptic current; NMDA, N-methyl-D-aspartate; NEM, N-ethylmaleimide; NO, Nitric
oxide; NT-4/5, neurotrophin factor 4/5; PDAc, phorbol-12,13-diacetate; PDBu, phorbol-12,13-dibutyrate; PKA, protein kinase A; PKC, protein
kinase C; PLC, phospholipase C; PTX, pertussis toxin; SCH-23390R, -( +)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-ben-
zazepine; SERCA, sarco-endoplasmic reticulum calcium pump; SKF-38393, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol; SNAP-25,
synaptosome associated protein of 25 kDa; SNARE, soluble NSF-attachment protein receptor; SV, synaptic vesicle; TeNT, tetanus neurotoxin;
TNF-a, tumour necrosis factor alpha; TTX, tetrodotoxin; VAMP, vesicle associated membrane protein; VIP, vasoactive intestinal peptide.
* Tel.: +33-5-57574085; fax: + 33-5-57574082.
E-mail address: alexandre.bouron@pcs.u-bordeauz2.fr (A. Bouron).

0301-0082/01/$ - see front matter 2001 Elsevier Science Ltd. All rights reserved.
PII: S 0 3 0 1 - 0 0 8 2 ( 0 0 ) 0 0 0 5 3 - 8
614 A. Bouron / Progress in Neurobiology 63 (2001) 613635

3.2.1. Ca2 + . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617


3.2.1.1. External Ca2 + . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
3.2.1.2. Intracellular Ca2 + stores . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
3.2.2. Other cations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
3.3. Protein kinase activators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
3.3.1. Phorbol esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
3.3.2. Forskolin, cAMP, 8Br-cAMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
3.3.3. 8Br-cGMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
3.4. Neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
3.4.1. Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
3.4.1.1. Metabotropic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
3.4.1.2. Ionotropic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
3.4.2. GABA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
3.4.3. Acetylcholine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
3.4.3.1. Nicotinic receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
3.4.3.2. Muscarinic receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
3.4.4. Norepinephrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
3.4.5. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
3.4.6. Adenosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
3.4.7. Histamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
3.4.8. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
3.5. Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
3.6. Clinically used drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
3.6.1. Antispychotic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
3.6.2. Antidepressant drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
3.6.3. Antiepileptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
3.6.4. Organic nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
3.7. Neurotrophins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
3.8. Hypoxia-ischemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
3.9. Neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
3.10. Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
3.11. Neurotoxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
3.12. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
3.12.1. Cyclothiazide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
3.12.2. Hypertonic solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
3.12.3. Bafilomycin A1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
3.12.4. Organophosphorus compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.12.5. N-ethylmaleimide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.12.6. Immunoglobulins (IgGs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.12.7. Ca2 + ionophores . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
3.12.8. pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628

4. Presynaptic facilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628

5. Presynaptic inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629

6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630

1. Introduction cally described as the main sites of chemical transmis-


sion. The invasion of axon terminals by an action
Although dendrites or soma can release chemical potential activates voltage-gated calcium channels. This
signals in a Ca2 + -dependent manner (Huang and Ne- leads to a rapid, brief and massive influx of Ca2 +
her, 1996; Kombian et al., 1997; Maletic-Savatic et al., nearby release sites. A plethora of studies demonstrated
1999; Zilberter et al., 1999), nerve terminals are classi- the central role played by Ca2 + in action potential-de
A. Bouron / Progress in Neurobiology 63 (2001) 613635 615

pendent neurotransmitter release (for a review see John- absence of presynaptic depolarization. Neurotransmit-
ston and Wu, 1995). The depolarisation-induced ters, exocytosed spontaneously or in response to an
elevation of the intracellular concentration of Ca2 + action potential, are released in packets called quanta.
([Ca2 + ]i ) increases the probability of fusion of the Each quantum is thought to represent a single synaptic
vesicular membrane with the presynaptic membrane vesicle (SV) and its neurotransmitter content gives rise
and the subsequent release of neurotransmitter into the to a miniature postsynaptic response. Therefore, quanta
synaptic cleft. Some authors have also suggested that, are the building blocks of the evoked responses.
in parallel with the action potential-induced Ca2 + en-
try, the depolarization of the presynaptic membrane
would also participate in the mechanisms triggering and 2. Presynaptic plasticity
controlling neurotransmitter release (Parnas et al.,
2000; but see Zucker and Haydon, 1988). Downstream Both processes of evoked and spontaneous transmit-
to the opening of voltage-gated Ca2 + channels (Catter- ter release are not constant. The modulation of the
all, 1998; Seagar et al., 1999), the action potential-de- strength of a synaptic connection is a fundamental
pendent release of chemical signals sets in motion a property of neuronal cells. Synaptic plasticity is re-
cascade of events involving Ca2 + ions, cytosolic fac- garded as a physiological process of crucial importance
tors, proteins of the plasma and vesicular membranes because short- and long-lasting changes in synaptic
as well as cytoskeleton elements. In the past few years, strength are thought to provide the molecular basis of
considerable progress has been made in characterizing learning and memory (Elgersma and Silva, 1999).
the proteins involved in transmitter release. According Presynaptically, several important factors control the
to the soluble attachment protein receptor (NSF)-at- strength of a synaptic connection. For instance (i) the
tachment protein receptor (SNARE) hypothesis of exo- size of the SVs, or (ii) their neurotransmitter content;
cytosis, vesicle SNAREs (v-SNAREs) such as vesicle (iii) the number of release sites; or (iv) the probability
associated membrane protein (VAMP)/synaptobrevin of quantal release at each site, can modulate synaptic
and synaptosome associated protein of 25 kDa (SNAP- transmission between nerve cells and their targets.
25), interact with a target SNARE (t-SNARE) of the The goal of this article is to review various secreta-
plasma membrane, syntaxin (Rothman, 1994). Experi- gogues and manoeuvres that presynaptically affect, on
ments performed with lipid bilayers demonstrated that a short time scale (seconds to minutes), action poten-
they can mediate membrane fusion (Weber et al., 1998). tial-independent release of neurotransmitters in the
Therefore, SNAREs constitute the core of the fusion hippocampus.
machinery and their cleavage by botulinum or tetanus
neurotoxins blocks synaptic transmission (Niemann et
al., 1994; Capogna et al., 1997; Humeau et al., 2000). 3. Modulation of spontaneous quantal release in the
However, a detailed molecular understanding of the hippocampus
sequences leading to exocytosis is still lacking. [For
recent reviews on the molecular machinery of the neu- Glutamate and g-aminobutyric acid (GABA) are the
ronal secretory apparatus, see (Augustin et al., 1999; main intrinsic hippocampal neurotransmitters (Vizi and
Augustine et al., 1999; Hughson, 1999)]. Kiss, 1998). Glutamatergic neurons are found in the
Beside action potential-evoked exocytosis, there is a dentate gyrus and CA1-CA3 fields. On the other hand,
vesicular release process not triggered by the depolari- interneurones are mainly GABAergic (Freund and
sation of the presynaptic nerve terminal. This electrical Buzaski, 1996). For a detailed description of the synap-
activity-independent release is called spontaneous be- tic organization of the hippocampus see (Brown and
cause the mechanisms triggering and controlling it are Zador, 1990). This review article focuses on electro-
not known. Spontaneous neurotransmitter release is physiological studies analyzing the modulation of spon-
observed in the presence of tetrodotoxin (TTX), a taneous neurotransmitter release in the presence of
highly specific blocker of voltage-gated Na+ channels, TTX. Changes in the frequency of spontaneous minia-
which prevents action potential initiation and propaga- ture postsynaptic signals are generally thought to reflect
tion. The electrical activity-independent exocytosis oc- a presynaptic change in release probability. However, a
curs at PNS and central nervous system (CNS) higher frequency of spontaneous signals can also de-
synapses and generates spontaneous excitatory or in- note postsynaptic changes (see below). Several authors
hibitory postsynaptic currents of small amplitudes found that a subpopulation of synapses do not exhibit
(Katz, 1969) also named miniature excitatory (or in- a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
hibitory) postsynaptic currents (mEPSCs or mIPSCs) (AMPA) receptor currents in response to synaptically
or minis (Bekkers and Stevens, 1989). They occur at a released glutamate (so-called silent synapses) (Malenka
low frequency (Bekkers et al., 1990; Forti et al., 1997) and Nicoll, 1997; Morales and Goda, 1999). The num-
which indicates the low probability of release in the ber of postsynaptic receptors is not constant (Liao et
616 A. Bouron / Progress in Neurobiology 63 (2001) 613635

al., 1995; Oliet et al., 1996) because postsynaptic densi- press the on-going exocytosis in cultured pyramidal
ties are dynamic structures (Turrigiano, 2000). For cells (Bouron, 1997).
instance, a quantitative electron microscopic analysis
showed that application of insulin to cultured mouse 3.1. Electrical acti6ity
hippocampal neurons triggers the rapid translocation of
GABAA channels from intracellular compartments to The electrical activity of the nerve terminal influences
the plasma membrane (Wan et al., 1997). This leads to the rate of spontaneous release. Single or repetitive
an enhanced frequency (and amplitude) of mIPSCs due action potentials elevate the frequency of mEPSCs
to the insertion of new functional GABAA channels in (Cummings et al., 1996; Goda and Stevens, 1994).
the postsynaptic site (Wan et al., 1997). In the following Protocols inducing long-term potentiation (LTP) and
article I review electrophysiological studies investigating long-term depression (LTD) increase or decrease, re-
the effect of secretagogues on the rate of spontaneous spectively, the frequency of miniature postsynaptic cur-
release under conditions where the amplitude and the rents. In microdot cultures of guinea-pig dentate
kinetics of miniature postsynaptic currents were un- granule neurons, tetanic stimulation triggers (a LTP of
changed and thus indicative of a predominantly presy- the evoked responses but also causes) a long-lasting
naptic site of modulation. augmentation of the mEPSC frequency (Tong et al.,
As noted above, in vivo, the mechanisms triggering 1996). By using MK-801, an irreversible inhibitor of
and controlling the spontaneous fusion of SVs are not N-methyl-D-aspartate (NMDA) receptors, they showed
understood. The TTX-resistant release does not usually that the tetanic stimulation-induced enhancement of the
reflect spontaneous [Ca2 + ]i changes since it also occurs basal release reflects the recruitment of previously silent
in nominally Ca2 + -free solution, or after blockade of synapses (Tong et al., 1996). In conclusion, there is no
voltage-gated Ca2 + channels with Cd2 + (see Section clear presynaptic contribution in the plasticity con-
3.2.1). The action potential-independent release is also trolled by the pairing of synaptic activation. For in-
not under the control of a tonically activated Gi/Go stance, 2-amino-5-phosphonovalerate (APV), an
protein since pre-treatment with pertussis toxin (PTX) NMDA receptor antagonist, blocks the pairing-induced
does not abolish the basal release (Boehm and Betz, LTP in CA1 neurons from guinea-pig hippocampal
1997). The spontaneous, Ca2 + -independent, fusion of slices (Oliet et al., 1996).
SVs seems to require actin filaments. Latrunculin B, an LTD induction protocols reduce the mEPSC fre-
inhibitor of actin polymerization, reduces the frequency quency and amplitude (Goda and Stevens, 1996; Caroll
of mEPSCs measured in CA1 pyramidal neurons in et al., 1999). Electrical stimulation leads to a reduction
slices (Kim and Lisman, 1999). On the other hand, in the number of postsynaptic AMPA receptors (Caroll
disruption of the microtubule network does not sup- et al., 1999). In addition, the LTD induction protocol

Table 1
Modulation of spontaneous release in the hippocampus (see text for references). P, o: augmentation or reduction of the frequency of miniature
currents, respectively, U: the frequency remains constant.

Acting on Frequency of Mechanism of action

mEPSCs mIPSCs

Electrical acti6ity
LTP induction protocois ? P NMDA receptors (postsynaptic induction ?)
LTD induction protocols ? U or o ?
Cations
External Ca2+ Ca2+ -sensor ? U or P U or P ?
Ca2+ from internal Ca2+ -sensor ? U or P U or P ?
stores
Ruthenium red External site P P Ca2+-independent mechanism
Gb3+ ? U or P ?
Pb2+ ? P P Ca2+-independent mechanism
Cd2+ U U /
Protein kinase acti6ators
Forskolin, cAMP, PKA P P Rabphilin-, RIM- and synaptobrevin-dependent ? Ca2+
8Br-cAMP -independent
Phorbol esters PKC P P ? Ca2+-, GAP-43 independent
8Br-cGMP ? P ?
A. Bouron / Progress in Neurobiology 63 (2001) 613635 617

Table 2
Effects of neurotransmitters on the frequency of miniature currents (see text for references)

Receptors activated Frequency of Mechanism of action

mEPSCs mIPSCs

Neurotransmitters
Glutamate MGIuRs o or U ?
Kainate receptors U or o PKC-dependent
GABA GABAB o o Ca2+-, PKA- independent, occluded by PKC
Acetylcholine Nicotinic P [Ca2+]-dependent
Muscarinic o ?
Muscarinic M1/M5 P PKC-dependent
Norepinephrine a-adrenergic U U /
b-adrenergic P ?
Dopamine D1 P PKA-dependent, Ca2+-independent
Adenosine A1 P o Ca2+-, PKA-, PKC-independent
Histamine H3? o ?
Serotonin U U /

seems to exert a direct presynaptic modulatory action When added in the presence of TTX, cadmium (Cd2 + ),
that reduces the basal release (Caroll et al., 1999). The a non-specific Ca2 + channel blocker, does not change
mechanism by which the pattern of electrical stimula- the frequency of spontaneous postsynaptic currents
tions of the nerve ending reduces action potential-inde- (Boehm and Betz, 1997; Capogna et al., 1993; McQuis-
pendent release is not known (Table 1). ton and Colmers, 1996; Wang et al., 1997). This makes
unlikely that the basal release is under the control of
3.2. Cations Ca2 + entry through voltage-gated Ca2 + channels.
However, in the spinal cord, blockers of low-threshold
3.2.1. Ca 2 + voltage-gated Ca2 + channels reduce the rate of mEPSC
occurrence (Bao et al., 1998).
3.2.1.1. External Ca 2 + . If the evoked neurotransmitter Manoeuvres that rapidly elevate [Ca2 + ]i nearby re-
release critically depends on the entry of Ca2 + through lease sites potently enhance the frequency of miniature
voltage-gated Ca2 + channels, the requirement of Ca2 + postsynaptic currents. For instance, application of the
in triggering the action potential-independent neuro- Ca2 + ionophore ionomycin increases the frequency of
transmitter release is less clear. Some authors have mIPSCs and mEPSCs (Capogna et al., 1996a) (see
reported that the frequency of miniature postsynaptic Section 3.12) (Table 5).
currents is not affected when the bath solution is Ca2 + entry through presynaptic ligand-gated recep-
switched to a nominally Ca2 + -free solution (Capogna tors can constitute an important Ca2 + source. For
et al., 1993; Scanziani et al., 1992; Sciancalepore et al., instance, activation of nicotinic presynaptic receptors
1998; Scholz and Miller, 1992), or to a nominally increases the frequency of miniature postsynaptic cur-
Ca2 + -free solution containing the Ca2 + chelator ethyl- rents in a Ca2 + -dependent manner (Gray et al., 1996;
ene glycol-bis(b amino-ethyl ether)-N,N,N%,N%-te- Nishizaki et al., 1999) (see Section 3.4.3.1) (Table 2).
traacetic acid (EGTA) (Capogna et al., 1996a). The Na+/Ca2 + exchanger is highly expressed in neu-
Contrary to these studies, other authors have reported rons (for a review see Blaustein and Lederer, 1999). The
that the removal of external Ca2 + reduces the fre- extrusion of Ca2 + through this ion transport protein is
quency of miniature postsynaptic currents (Braga et al., driven by the Na+ gradient. Therefore, when the driv-
1999; Li et al., 1998a; Mozrzymas et al., 1999). On the ing force for Na+ or the membrane potential varies, the
other hand, increasing the external concentration of exchanger can operate in the reverse mode (Ca2 + en-
Ca2 + ([Ca2 + ]o) from 2 to 4 mM enhances the sponta- try). Ca2 + signalling through the Na+/Ca2 + exchanger
neous quantal release (Grassi et al., 1994) (Table 1). has been thought to influence neurotransmitter release
These results suggest that under some conditions, basal (Blaustein and Lederer, 1999). Intracellular acidifica-
release can be influenced by [Ca2 + ]o. In hippocampal tion, such as that produced by weak acids like propi-
neurons, dihydropyridine-sensitive (or L-type) Ca2 + onate, is accompanied by a modest and short-lasting
channels have been reported to mediate a sustained elevation of the mEPSC frequency (Trudeau et al.,
Ca2 + entry at resting membrane potentials (Magee et 1999). Upon washout of propionate with normal saline,
al., 1996). This resting Ca2 + influx could be involved in there is a rapid rebound alkalinization during which a
the action potential-independent exocytosis of SVs. transient but strong augmentation of the mEPSC fre-
618 A. Bouron / Progress in Neurobiology 63 (2001) 613635

quency is observed (Trudeau et al., 1999). By of hippocampal neurons in culture are empty at rest
combining electrophysiological recordings, [Ca2 + ]i and (Irving and Collingridge, 1998; Bouron, 2000). Bath
[Na+]i imaging techniques, Trudeau and colleagues applications of caffeine, which releases Ca2 + from caf-
(1999) showed that the recovery from acidification leads feine/ryanodine sensitive stores, reduce the frequency of
to a massive entry of Ca2 + through the Na+/Ca2 + mIPSCs (Savic and Sciancalepore, 1999). But this de-
exchanger. Therefore Ca2 + movements through the crease may reflect a postsynaptic change since caffeine
Na+/Ca2 + exchanger can influence the action poten- also blocks chloride currents through GABAA chan-
tial-independent neurotransmitter release (see also nels. However, brief pressure pulses of caffeine increase
Reuter and Porzig, 1995; Bouron and Reuter, 1996). It the frequency of mIPSCs without affecting their ampli-
is however, important to note that immunocytochemi- tude (Savic and Sciancalepore, 1999) (Table 5). Im-
cal experiments performed on isolated calyx nerve ter- munohistochemical studies revealed that IP3- and
minals show that the Na+/Ca2 + exchanger of the caffeine-sensitive Ca2 + stores are differentially spatially
NCX1 type is not expressed nearby release sites (Juhas- located. IP3 receptors are more abundant in dendrites
zova et al., 2000). whereas caffeine-sensitive compartments are found in
Store-operated or capacitative Ca2 + entry has axons (Sharp et al., 1993; Seymour-Laurent and Barish,
mainly been analyzed in non-excitable cells. But this 1995). Therefore, only Ca2 + stores located nearby the
entry pathway is also present in excitable cells such as sites of exocytosis are likely to influence transmitter
PC12 cells (Clementi et al., 1992), neuroblastoma cells release. The work of Savic and Sciancalepore (1999)
(Mathes and Thompson, 1994; Takemura et al., 1991), suggests that caffeine-sensitive compartments might be
adrenal chromaffin cells (Fomina and Nowycky, 1999), located at release sites. Mitochondrial Ca2 + stores have
DRG neurons (Usachev and Thayer, 1999), olfactory been thought to modulate basal spontaneous glutamate
receptor neurons (Zufall et al., 2000) and hippocampal release. FCCP, a mitochondrial inhibitor, elevates
neurons (Bouron, 2000). So far, the influence of the [Ca2 + ]i and increases the mEPSC frequency (Trudeau
store-operated Ca2 + entry on spontaneous neurotrans- et al., 1996a; Scotti et al., 1999). Thus, the release of
mitter release has never been documented. However, it Ca2 + from intraterminal Ca2 + stores is able to increase
is worth mentioning that it modulates exocytosis in the rate of action potential-independent transmitter
adrenal chromaffin cells (Fomina and Nowycky, 1999). release.

3.2.1.2. Intracellular Ca 2 + stores. The release of Ca2 + 3.2.2. Other cations


from caffeine-, IP3-sensitive Ca2 + compartments or Various cations can affect the spontaneous quantal
from mitochondria is believed to affect the strength of release of neurotransmitters. For instance, ruthenium
evoked responses (Chittajallu et al., 1996; Frenguelli et red, a polyvalent cation that is impermeant to intact
al., 1996; Berridge, 1998). Many substances such as plasma membranes, causes a robust and long-lasting
volatile anaesthetics, tricyclic antidepressant drugs, neu- augmentation of the frequency of miniature GABAer-
rotransmitters, or neurotrophins like the brain-derived gic (Trudeau et al., 1996a; Sciancalepore et al., 1998)
neurotrophic factor (BDNF) can release Ca2 + from and glutamatergic currents (Bouron and Reuter, 1999)
intracellular stores. However, only a few studies have (Table 1). This up-regulation is not affected by remov-
shown that the frequency of miniature postsynaptic ing external Ca2 + or by depleting intracellular [Ca2 + ]i
currents can be modulated by the release of Ca2 + from stores with thapsigargin (Trudeau et al., 1996a). Cal-
intracellular compartments in hippocampal neurons. cium imaging experiments indicate that ruthenium red
Ca2 + pumps of the sarco- endoplasmic reticulum are does not produce detectable [Ca2 + ]i changes in den-
irreversibly blocked by submicromolar concentrations drites and somata (Trudeau et al., 1996a). Application
of thapsigargin (Treiman et al., 1998). This results in a of the membrane-impermeant molecule heparin reverses
slow release of Ca2 + from intracellular stores. In cul- the ruthenium red-induced augmentation of mIPSC
tured hippocampal neurons, thapsigargin fails to affect frequency by removing RR from the membrane. There-
the basal frequency of miniature postsynaptic currents fore, ruthenium red modulates synaptic efficacy in a
measured in pyramidal cells (Bouron and Reuter, 1997; Ca2 + -independent manner by interacting with an exter-
Trudeau et al., 1996b). However, thapsigargin enhances nal site. Electron microscopy observations show that it
the frequency of mIPSCs in CA3 pyramidal neurons markedly stimulates spontaneous transmitter release
from hippocampal slices (Savic and Sciancalepore, without perturbing the ultrastructural integrity of the
1999) (Table 5). This effect is only observed with high synapse (Trudeau et al., 1996a). The mechanism of
concentrations (]10 mM) of the Ca2 + pump blocker action of ruthenium red is not understood but this
and disappears in nominally Ca2 + -free solutions. The cation seems to interfere with the secretory apparatus.
inability of thapsigargin to enhance basal spontaneous Under certain experimental conditions the lanthanide
transmitter release in cultured hippocampal neurons gadolinium (Gd3 + ) can also enhance spontaneous neu-
could be due to the fact that intracellular Ca2 + stores rotransmitter release (Capogna et al., 1996b). When
A. Bouron / Progress in Neurobiology 63 (2001) 613635 619

applied in the presence of TTX, Gd3 + has no effect on Madison, 1993). In addition, phorbol esters affect spon-
the mEPSC or mIPSC frequency. However, when it is taneous release without inducing detectable [Ca2 + ]i
added prior to TTX, it strongly increases the frequency changes (Bouron, 1997; Yawo, 1999). A PKC-depen-
of miniature GABAergic and glutamatergic synaptic dent modulation is also seen when the cells are loaded
currents. Gd3 + , which can substitute for Ca2 + in con- with BAPTA to suppress [Ca2 + ]i signals (Bouron and
trolling exocytosis (Molgo et al., 1991), is believed to Reuter, 1997). Therefore, PKC activators promote neu-
enter presynaptic nerve terminals during the sponta- rotransmitter release via a Ca2 + -independent mecha-
neous firing activity-induced depolarization of the neu- nism. The PKC-dependent modulation could be
ron (Capogna et al., 1996b) (Table 1). mediated by PKC-o, the only Ca2 + -insensitive PKC
A very small augmentation of the miniature fre- found in hippocampal nerve endings (McGinty et al.,
quency is observed in the presence of the divalent 1991).
cation lead (Pb2 + ) (Braga et al., 1999). This effect Electrophysiological measurements combined with
develops within 2 min and does not disappear in the optical detection of SV trafficking indicate that phorbol
absence of external Ca2 + . In addition, the Ca2 + chela- esters increase both the size of the readily releasable
tor EDTA does not block the Pb2 + -dependent modula- pool of SVs as well as the rate at which this pool refills
tion of the spontaneous release. Braga et al. (1999) (Stevens and Sullivan, 1998). Similar conclusions have
concluded that Pb2 + is stimulating the exocytosis of been reached in chromaffin cells (Gillis et al., 1996) and
glutamate and GABA in a Ca2 + -independent manner retinal bipolar cells (Minami et al., 1998). These results
through an intracellular (but uncharacterized) mecha- stand in contrast to those obtained in chick ciliary
nism (Table 1). ganglion neurons where PKC does not change the size
of the readily releasable pool but upregulates the Ca2 +
3.3. Protein kinase acti6ators sensitivity of the exocytotic fusion process (Yawo,
1999). A molecular description of PKC action on the
At the presynaptic site, the phosphorylation/dephos- spontaneous (as well as the evoked) exocytosis is still
phorylation state of ion channels and proteins of the lacking. FI, B-50 or neuromodulin (GAP-43) is a
exo/endocytic cycle can influence the strength of a widely expressed PKC substrate. It is found at presy-
synaptic connection (Capogna, 1998; Boxall and Lan- naptic sites where its phosphorylation might affect neu-
caster, 1998; Turner et al., 1999). Among the different rotransmitter release (Benowitz and Routtenberg,
protein kinases that are thought to exert a prominent 1997). This was verified by using GAP-43 deficient mice
role in modulating the release, protein kinases A (PKA) (Capogna et al., 1999). However, this study clearly
and C (PKC) are, with the Ca2 + /calmodulin-dependent showed that in GAP-43-deficient mice the phorbol ester
PK, the major enzymes implicated in various forms of PDAc still increases the frequency of mEPSCs. This
short- and long-term plasticity. demonstrates that GAP-43 is not involved in the rapid
PKC-dependent augmentation of the release. Dynamin,
3.3.1. Phorbol esters SNAP-25 and the NSF-soluble attachment proteins a-,
The PKC family is composed of 10 structurally re- b-, g-SNAPs contain PKC phosphorylation sites (Ca-
lated serine-threonine protein kinases (Ron and Ka- pogna, 1998). So far, there is no experimental evidence
zanetz, 1999). Most PKC isoforms are activated by demonstrating that these presynaptic proteins mediate
diacylglycerol (DAG). The highly hydrophilic tumour- the PKC-dependent modulation.
promoting agents phorbol esters share the same binding Interestingly, phorbol esters and DAG can also inter-
site on PKC as DAG and are therefore commonly used act with intracellular receptors having no kinase activ-
to activate the enzymatic activity of DAG-sensitive ity (Ron and Kazanetz, 1999). This is for example the
PKCs. Malenka and Nicoll (1997), demonstrated that case of the Unc-13 gene product, identified in C. ele-
phorbol-12,13-dibutyrate (PDBu) and phorbol-12,13- gans, and its mammalian homologue Munc-13. They
diacetate (PDAc), two phorbol esters, increase the fre- are likely to play a crucial role in neurotransmitter
quency of mIPSCs (Table 1). These experiments were release (Betz et al., 1998; Tokumaru and Augustine,
performed with rat hippocampal slices but similar ob- 1999; Augustin et al., 1999). For instance, Munc-13 is
servations have been made with mass cell and organ- involved in a maturation process that occurs down-
otypic slice cultures. Phorbol esters, via PKC stream to the docking of glutamatergic SVs (Augustin
activation, produce a rapid and long lasting augmenta- et al., 1999). In a recent report, (Hori et al. 1999)
tion of the spontaneous TTX-resistant release (Finch showed that Mid, a peptide that blocks the interaction
and Jackson, 1990; Capogna et al., 1995; Jarolimek and Doc2a-Munc13-1, attenuates the phorbol ester effect
Misgeld, 1997; Parfitt and Madison, 1993; Yamamoto on synaptic transmission. Two Doc2 isoforms (a, b)
et al., 1987). This modulation occurs in Ca2 + -free have been identified. Doc2a is not essential for Ca2 + -
solution (Finch and Jackson, 1990), or in the presence dependent neurotransmitter release but is thought to
of Cd2 + (Capogna et al., 1995 but see Parfitt and modulate excitatory synaptic transmission (Sakaguchi
620 A. Bouron / Progress in Neurobiology 63 (2001) 613635

et al., 1999). It interacts with Munc-13-1 in a Ca2 + , there is a region-specific phosphorylation of some PKA
phorbol ester and DAG-dependent manner (Orita et substrates. For instance, Lonart and Sudhof (1998)
al., 1997). It is worth mentioning that PKC activation found a forskolin-dependent phosphorylation of
does not always promote neurotransmitter release. For rabphilin in CA3 but not in CA1 synaptosomes. Down-
instance, Rodriguez-Moreno and Lerma (1998) found stream to PKA, rabphilin and RIM seem to couple
that activation of kainate receptors, a subtype of activated PKA and the secretory apparatus (Lonart et
ionotropic glutamate receptors, reduces the frequency al., 1998). At the Drosophila neuromuscular junction,
of mIPSCs in hippocampal brain slices. The down- experiments performed with genetically modified em-
stream signalling cascade involves phospholipase C bryos lacking the neuronal synaptobrevin gene show
(PLC) and PKC (see Section 3.4.1.2). The mechanism that PKA activators do not increase the frequency of
of PKC activation as well as the PKC isoforms and the mEPSCs (Yoshihara et al., 1999). Thus, synaptobrevin
downstream PKC targets might critically determine the appears essential for the PKA-dependent facilitation of
overall effects of PKC activation on the spontaneous spontaneous neurotransmitter release in Drosophila.
quantal release.
3.3.3. 8Br-cGMP
3.3.2. Forskolin, cAMP, 8Br-cAMP In cultured neurons from dissociated neonatal rat
PKA is activated by cAMP and phosphorylates and hippocampi, the addition of 8Br-cGMP (50 100 mM)
a plethora of proteins on serine/threonine residues. or a presynaptic injection of cGMP elevates the fre-
Forskolin or 8Br-cAMP is frequently used to activate quency of mEPSCs (Arancio et al., 1995). Unfortu-
PKA activity. They rapidly augment the rate of sponta- nately, the downstream signalling pathway has not been
neous release (Greengard et al., 1993; Chavez-Noriega investigated (Table 1). This stands in contrast with
and Stevens, 1994; Capogna et al., 1995; Trudeau et al., experiments carried out with mass cell cultures of
1996b; Jarolimek and Misgeld, 1997) (Table 1). Appli- hippocampal neurones prepared from rat embryos
cation of Cd2 + does not affect the PKA-dependent where 8Br-cGMP (1 mM) does not change the fre-
potentiation showing that the enhanced neurotransmit- quency of mEPSCs (Pan et al., 1996).
ter release is not due to an influx of Ca2 + through
voltage-gated Ca2 + channels (Capogna et al., 1995). 3.4. Neurotransmitters
PKA and PKC have additive effects on spontaneous
release (Capogna et al., 1995; Bouron and Reuter, As shown above, the activity of presynaptic nerve
1999), indicating that these two kinases recruit indepen- terminals is subject to external modulatory influences
dent target proteins. In the hippocampus, PKA activa- via endogenous or exogenous agents. Nerve terminals
tion increases the number of active release sites. posses receptors for the exocytosed neurotransmitter
However, this effect has a slow onset of action and (autoreceptors) but also express receptors responding to
depends on protein synthesis (Ma et al., 1999). There- neurotransmitters released by neighboring neurons (het-
fore, it most likely cannot account for the rapid en- eroreceptors). Autoreceptors having excitatory or in-
hancement of the miniature frequency induced by PKA hibitory effects on release mediate positive or negative
activators. In the cerebellum, cAMP rapidly enhances, feedback loops that allow neurons to control the release
in a PKA-dependent manner, the probability of release of their own neurotransmitters (autoregulation). The
(p) (Chen and Regehr, 1997), the spontaneous turnover activation of heteroreceptors constitutes another impor-
of SVs at active synapses and the number of functional tant mechanism of presynaptic modulation. For a fur-
release sites (Chavis et al., 1998). ther discussion on presynaptic receptors see (Thompson
PKA activation is thought to directly affect the secre- et al., 1993; McGehee and Role, 1996; Sanchez-Prieto
tory apparatus. In the hippocampus, cAMP increases et al., 1996; Langer, 1997; Miller, 1998; MacDermott et
the number of readily releasable vesicles (Lonart and al., 1999).
Sudhof 1998), without increasing neither the number of
morphologically docked vesicles nor the number of 3.4.1. Glutamate
active synaptic terminals (Trudeau et al., 1996b). PKA
acts on an early step leading to neurotransmitter release 3.4.1.1. Metabotropic receptors. Up to eight metabo-
(Trudeau et al., 1998). It increases the Ca2 + coopera- tropic glutamate receptors (mGluRs) have been charac-
tivity for release and promotes the interaction between terized (Schoepp et al., 1999). Based on their amino
the Ca2 + -sensing module and the secretory apparatus acid composition and their downstream coupling mech-
(Trudeau et al., 1998). Biochemical studies have charac- anisms, they are further subdivided into three families:
terised several ubiquitous presynaptic PKA substrates mGluRI (mGluR1, mGluR5), mGluRII (mGluR2,
such as rabphilin, RIM, (two Rab3a effectors), a- mGluR3), and mGluRIII (mGluR4, mGluR7,
SNAP or the synapsins (Greengard et al., 1993; Ca- mGluR8) (Schoepp et al., 1999). All but mGluR6 are
pogna, 1998; Lonart and Sudhof, 1998). Interestingly, found in the hippocampus. Glutamatergic receptors of
A. Bouron / Progress in Neurobiology 63 (2001) 613635 621

the mGluRI family are mainly present on postsynaptic sion. However, one cannot completely exclude the pres-
structures (Ottersen and Landsend, 1997) and their ence of presynaptic NMDA receptors since the NMDA
activation with the mGluRI agonist DHPG (100 mM) receptor subunit 1 has been found on hippocampal
does not change the frequency of mEPSCs in CA1 presynaptic nerve terminals (Siegel et al., 1994).
pyramidal neurons (Gereau and Conn, 1995). A similar The presence of functional presynaptic ionotropic
conclusion has been reached with the mGluRl agonist glutamate receptors has been suggested. For instance,
quisqualate (up to 10 mM) which has no effect on the experiments performed with hippocampal synapto-
mIPSC frequency measured in CA3 pyramidal somes provided evidence for the presence of presynaptic
neurones (Poncer et al., 1995). DHPG and LY354740, NMDA receptors (Breukel et al., 1998). Activation of
another mGluRl agonist, do not change the frequency these synaptosomal NMDA receptors stimulates the
of mEPSCs measured at glutamatergic autapses release of GABA and glutamate. It is worth indicating
(Bushell et al., 1999). DHPG is also not affecting the that in cerebellar interneurones and Purkinje cells, acti-
spontaneous GABA release in autaptic hippocampal vation of NMDA receptors increases the frequency of
neurones (Bushell et al., 1999) (Table 2). mIPSCs (but not mEPSCs) (Glitsch and Marty, 1999).
mGluRII and mGluRIII have a pre- or perisynaptic Bureau and Mulle (1998) provided functional evidence
expression (Lujan et al., 1996; Shigemoto et al., 1997; for the existence of presynaptic AMPA receptors in
Ottersen and Landsend, 1997). The mGluRIII agonist cerebellar stellate cells and located nearby GABA re-
L-AP4 (50 mM) does not affect the frequency of lease sites. For instance, the AMPA receptor agonist
mEPSCs in CA3 pyramidal neurons (Cotman et al., domoate increases the frequency of mIPSCs even in the
1986) but it reduces (with 1 mM) the frequency of presence of Cd2 + (Bureau and Mulle, 1998). However,
mEPSCs in CA1 pyramidal neurones (Gereau and no similar observations have been made so far in the
Conn, 1995). In autaptic hippocampal neurones from hippocampus.
foetal rats, L-AP4 (10 mM) depresses the frequency of Kainate receptors, another family of ionotropic glu-
mEPSCs (Bushell et al., 1999) whereas 300 mM L-AP-4 tamate receptors, are expressed in many CNS structures
like the hippocampus (Lerma, 1999). They are found
does not change the frequency of mEPSCs in autaptic
pre- and postsynaptically but their physiological func-
neurones from neonatal rats (OConnor et al., 1999).
tion is still unclear. Recent experiments showed that
DCG-IV (1-3 mM), a specific agonist of mGluRII
kainate receptors play a crucial role in synaptic plastic-
receptors depresses the spontaneous release of GABA
ity at mossy fiber-CA3 synapses (Bortolotto et al.,
(Poncer et al., 1995) and glutamate (Kamiya and
1999). They reduce the spontaneous TTX-resistant
Ozawa, 1999) in CA3 pyramidal neurones.
GABA release from hippocampal interneurones in
1S,3R-ACPD ( 550 mM), which activates most
slices (Rodriguez-Moreno et al., 1997; Rodriguez-
selectively mGluRII than mGluRI and mGluRIII,
Moreno and Lerma, 1998; Rodriguez-Moreno et al.,
reduces the mEPSC frequency without affecting the 2000) (Table 2). This effect seems to involve a metabo-
mIPSC frequency in CA1 pyramidal neurones tropic function and is mediated via PLC and PKC
(Sciancalepore et al., 1995; Morishita et al., 1997). activation. By contrast, activated kainate receptors do
1S,3R-ACPD has no effect on the mIPSC frequency in not change the frequency of miniature postsynaptic
hippocampal pyramidal neurones in culture currents measured in CA1 and CA3 pyramidal neu-
(Fitzsimonds and Dichter, 1996). However, when used rones (Castillo et al., 1997; Cossart et al., 1998; Bureau
at higher concentrations (]50 mM) 1S,3R-ACPD can et al., 1999).
depress the mIPSC frequency measured in CA1 An increasing body of evidence suggests the existence
pyramidal neurones. This effect occurs even in of an astrocyte-to-neurone signalling (Araque et al.,
nominally zero Ca2 + (Poncer et al., 1995). In 1999). Selective (mechanical or electrical) stimulation of
conclusion, presynaptic mGluRII-III can exert an astrocytes elevates their basal [Ca2 + ]i. This Ca2 + signal
inhibitory modulatory action on the spontaneous triggers the release of glutamate from astrocytes which,
synaptic activity (Table 2). Unfortunately, the coupling via the activation of NMDA receptors, augments the
mechanism linking presynaptic mGluRs and the frequency of mEPSCs or mIPSCs (Araque et al., 1998;
secretory apparatus is not known. Kang et al., 1998). This occurs in mixed cell cultures of
hippocampal neurones and astrocytes as well as in CA1
3.4.1.2. Ionotropic receptors. Local application of gluta- pyramidal neurones from hippocampal slices. The
mate produces a persistent increase in the frequency of Ca2 + -dependent release of glutamate is therefore not a
mEPSCs (Malgaroli and Tsien, 1992). This form of unique property of neuronal cells. This astrocyte-to-
synaptic plasticity requires NMDA receptor activity neurone signalling could be activated by prostaglandin
which suggests a postsynaptic locus of glutamate action E2 (PGE2) or the tumour necrosis factor-a (TNF-a)
and a retrograde signalling pathway. This will not be (Grassi et al., 1994; Sanzgiri et al., 1999). Nanomolar
discussed in the present review describing examples of concentrations of TNF-a, a cytokine secreted by astro-
synaptic plasticity having a presynaptic site of expres- cytes, irreversibly increase the frequency of mIPSCs
622 A. Bouron / Progress in Neurobiology 63 (2001) 613635

(Grassi et al., 1994). The signal transduction pathway hippocampus (a7-, a2b4-containing receptors) (Alkon-
downstream to the TNF-a receptors is not known but don et al., 1997). Activation of presynaptic nicotinic
might involved PLC or PLA2 activation. Recent experi- receptors promotes the entry of Ca2 + which triggers
ments have shown that the release of glutamate from neurotransmitter release (Gray et al., 1996) (Table 2).
astrocytes is not due to a reverse operation of gluta- The nicotinic-dependent modulation of glutamate re-
mate transporters (Araque et al., 2000). In addition, lease can be potentiated by arachidonic acid (Nishizaki
these authors raised the interesting hypothesis of a et al., 1999). The PKC inhibitor GF109203X blocks
Ca2 + - and vesicular-dependent glutamate exocytosis. this effect. Nishizaki et al., (1999) concluded that
Indeed, bafilomycin A1 and botulinum neurotoxin B arachidonic acid enhances the activity of presynaptic
(BoNT/B) which, respectively, inhibits the vesicular nicotinic receptors. However, it would be interesting to
ATPase and cleaves synaptobrevin, abolish the Ca2 + - determine the effect of arachidonic acid (without a
dependent glutamate release from astrocytes without nicotinic receptor agonist) on the spontaneous quantal
altering astrocytic Ca2 + signals (Araque et al., 2000). release of neurotransmitters in the hippocampus. Func-
tional data indicate that arachidonic acid can activate
3.4.2. GABA PKC in the hippocampus (Keyser and Alger, 1990).
Activation of GABAB receptors was thought to exert Activated PKC can, in turn, promote TTX-resistant
a selective effect on glutamatergic nerve terminals since neurotransmitter release (see Section 3.3.1). PKC and
baclofen, an agonist of GABAB receptors, reduces the Ca2 + entry through presynaptic nicotinic receptors
frequency of mEPSCs (Scanziani et al., 1992) without could have additive effects on the quantal release that
changing the frequency of mIPSCs (Cohen et al., 1992; would explain the arachidonic acid-dependent enhance-
Scanziani et al., 1992; Doze et al., 1995). However, ment of the nicotinic-induced augmentation of the
mEPSC frequency.
experiments performed with the active enantiomer (R)-
( )-baclofen showed that this GABAB receptor ago-
3.4.3.2. Muscarinic receptors. Experiments testing the
nist reduces the frequency of mIPSCs in a
implication of hippocampal muscarinic receptors have
concentration-dependent manner (Jarolimek and Mis-
led to opposing results (Table 2). Methacholine (10
geld, 1997). (R)-( )-baclofen still exerted its modula-
mM) reduces the mEPSC frequency by 50% in organ-
tory action in the presence of Ba2 + and Cd2 + ,
otypic slices in culture (Scanziani et al., 1992). On the
suggesting that it acts via a Ca2 + -independent mecha-
other hand, carbachol (50 200 mM) produces a strong
nism. Interestingly, PKC activation with phorbol esters
elevation of the mEPSC frequency in hippocampal
partially abolishes the (R)-( )-baclofen-dependent re-
neurones in culture (Bouron and Reuter, 1997, 1999).
duction of the mIPSC frequency. On the other hand, This latter effect involved M1/M5-type muscarinic re-
PKA activation with forskolin does not occlude the ceptors coupled to PTX-sensitive G-proteins and PKC
(R)-( )-baclofen response (Jarolimek and Misgeld, activation. The carbachol-dependent modulation is sup-
1997) (Table 2). pressed by adenosine (Bouron and Reuter, 1997) and
not occluded by the D1-dopamine receptor agonist 1-
3.4.3. Acetylcholine phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol
(SKF-38393) (Bouron and Reuter, 1999) (Section
3.4.3.1. Nicotinic receptors. Glutamatergic hippocampal 3.4.5).
neurones express nicotinic receptors that are located at
or near release sites (Wonnacott, 1997; Jones et al., 3.4.4. Norepinephrine
1999). Applications of nicotinic receptor agonists (in Norepinephrine does not affect the rate of sponta-
the presence of muscarinic receptor antagonists) elevate neous neurotransmitter release in CA3 (Scanziani et al.,
the frequency of spontaneous miniature postsynaptic 1993) and CA1 pyramidal neurones (Doze et al., 1991;
currents. For instance, nicotine transiently increases the Bergles et al., 1996) (Table 2). Similar results have been
frequency of mEPSCs (in CA1 and CA3 pyramidal found with autaptic neurones. and mass cell cultures
neurones, Gray et al., 1996), and the frequency of (Boehm, 1999). In contrast, isoproterenol, a b-adrener-
mPSCs (in CA1 pyramidal cells and interneurones, gic receptor agonist, increases the frequency of mEP-
Alkondon et al., 1997). Nicotinic receptor agonists SCs recorded in CA1 pyramidal neurones (Gereau and
rapidly enhance the frequency of mEPSCs in Conn, 1994). The signalling messengers downstream to
hippocampal neurones in culture (Radcliffe and Dani, the b-adrenergic receptors have not been characterized.
1998). This effect disappears in the absence of external Since b-adrenergic receptors are positively coupled to
Ca2 + . Kinetic and pharmacological analyses of the adenylate cyclase it is tempting to speculate that iso-
nicotine-induced currents revealed the heterogeneity of proterenol promotes the spontaneous glutamate release
the nicotinic receptor subtypes expressed in the via a cAMP/PKA-dependent mechanism.
A. Bouron / Progress in Neurobiology 63 (2001) 613635 623

3.4.5. Dopamine the basal release but also the release triggered by Ca2 + -
Activation of D1 dopamine receptors stimulates the dependent and Ca2 + -independent secretagogues. The
formation of cAMP (Stoof and Kebabian, 1981). SKF- effectors activated in response to the stimulation of A1
38393, a D1 dopamine receptor agonist, produces a receptors are not known. Increasing amounts of evi-
concentration-dependent elevation of the mEPSC fre- dence suggest that trimeric G proteins modulate mem-
quency in cultured hippocampal neurones (Bouron and brane trafficking (Gasman et al., 1998). In chromaffin
Reuter, 1999) (Table 2). This effect is blocked by the D1 cells, Go controls exocytosis via Rho and a Rho-depen-
receptor antagonist -(+)-7-chloro-8-hydroxy-3-methyl- dent phosphatidylinositol 4-kinase (Gasman et al.,
1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH- 1998). It would be interesting to verify whether such a
23390) and by PKA inhibitors. In the presence of a D2 mechanism also operates in CNS neurones. Linial et al.,
receptor antagonist, dopamine also increases the fre- (1997) found that in rat synaptosomes, muscarinic au-
quency of mEPSCs. Ruthenium red or carbachol does toreceptors bind to syntaxin, SNAP-25, synaptotagmin,
not occlude the SKF-38393 action. Ruthenium red and VAMP. This interaction is voltage-dependent (Lin-
stimulates the spontaneous neurotransmitter release by ial et al., 1997). This finding raises the possibility that
an unknown Ca2 + -independent mechanism (see Section other neurotransmitter receptors could be associated
3.2.2) whereas carbachol promotes spontaneous neuro- with proteins of the secretory core complex. It would be
transmitter release via a PKC-dependent mechanism of importance to know whether adenosine receptors
(see Section 3.4.2). In each instance, SKF-38393 further co-precipitate with SNARE proteins. This would help
increases the mEPSC frequency measured in the pres- elucidating the A1 adenosine receptor-dependent sig-
ence of ruthenium red or carbachol (Bouron and nalling pathway.
Reuter, 1999). This result indicates that these secreta-
gogues promote glutamate release via distinct presynap- 3.4.7. Histamine
tic mechanisms of action. In rat hippocampal slices, histamine slightly de-
presses spontaneous glutamate release in dentate gyrus
3.4.6. Adenosine granule cells. Indeed, 10 mM histamine very slightly
Adenosine is a potent neuromodulator. In the reduces the frequency of mEPSCs (Brown and Haas,
hippocampus, activation of A1-type adenosine recep- 1999) (Table 2). However, it strongly blocks evoked
tors inhibits spontaneous release via PTX-sensitive G responses. This latter effect is due to the activation of
proteins in hippocampal neurones from embryonic and H3 receptors and involves downstream protein kinases
neonatal rats (Scholz and Miller, 1992; Bouron and (Brown and Haas, 1999). Unfortunately, the identity of
Reuter, 1997) and via PTX-insensitive G proteins in the histamine receptors implicated in the small reduc-
adult cells (Scanziani et al., 1992) (Table 2). Down- tion of the mEPSC frequency as well as the down-
stream to the G-protein coupled A1 receptor, the sig- stream intracellular messengers have not been studied.
nalling messengers remain to be identified. Adenosine
inhibits release in the presence of Cd2 + , independently 3.4.8. Serotonin
of its action on voltage-gated Ca2 + channels (Scanziani Experiments performed with rat hippocampal slices
et al., 1992; Scholz and Miller, 1992). A1 receptors are showed that serotonin does not affect the spontaneous
negatively coupled to adenylate cyclase. Since activa- quantal release from interneurones to CA1 pyramidal
tion of PKA, with forskolin or 8Br-cAMP, increases neurones (Ropert and Guy, 1991) (Table 2).
the frequency of miniature currents (see Section 3.3.2),
adenosine could depress the spontaneous release by 3.5. Cannabinoids
inhibiting cAMP production. However, there is no
experimental data showing that a tonically activated Two subtypes of cannabinoid receptors have been
PKA regulates the basal release. In addition, adenosine identified, CB1 and 2. WIN55,212-2, a potent can-
reduces the frequency of mEPSCs whether PKA is nabinoid receptor agonist, reduces the frequency of
activated or inhibited (Bouron, 1999). In conclusion, mEPSCs in autaptic neurones in culture (Sullivan,
activated A1 adenosine receptors depress synaptic 1999). Experiments performed with mice hippocampal
transmission in a Ca2 + -independent manner via a slices showed that activation of CB1-type receptors
cAMP/PKA-independent pathway. Ionomycin, alpha- decreases the frequency of mEPSCs in CA1 pyramidal
latrotoxin (a-LTx), Gd3 + , phorbol esters, or ruthenium neurones (Misner and Sullivan, 1999) (Table 3). The
red stimulate the spontaneous release via Ca2 + -depen- mechanism underlying this inhibition is not understood.
dent or Ca2 + -independent mechanisms. In each in- Since cannabinoid receptors are negatively coupled to
stance, adenosine suppresses their stimulatory action cAMP it would be interesting to determine whether
(Capogna et al., 1996b; Trudeau et al., 1996b; Bouron, CB1-subtype receptors activation affects synaptic trans-
1999). Therefore, this purine recruits a PKA-indepen- mission by inhibiting the cAMP/PKA-dependent sig-
dent signalling pathway that potently inhibits not only nalling pathway. However, as discussed above, there is
624 A. Bouron / Progress in Neurobiology 63 (2001) 613635

no experimental data showing a tonically activated tinic and NMDA receptors (Rana et al., 1993;
PKA. It would be important to determine if adenosine Reynolds and Miller, 1988). In addition, they stimulate
and cannabinoids have additive effects or whether they PLC activity and IP3 production (Fukuda et al., 1994;
depress synaptic transmission via independent sig- Osborne, 1988). Measurements of [Ca2 + ]i changes
nalling mechanisms. showed that they elevate [Ca2 + ]i (Shimizu et al., 1993;
Bouron and Chatton, 1999) most likely by recruiting
3.6. Clinically used drugs Ca2 + from IP3-sensitive stores. This latter finding
showing that they stimulate PLC activity suggested that
3.6.1. Antispychotic drugs they could activate PKC activity. This was verified in
Chlorpromazine is an antipsychotic drug that is clas- cultured rat hippocampal neurones where therapeutic
sically described as a blocker of D2-dopamine receptors. concentrations of desipramine (] 10 mM) dramatically
However, this phenothiazine also blocks many neuro- increases the frequency of mEPSCs in a concentration-
transmitter receptors. At the neuromuscular junction it dependent manner (Bouron and Chatton, 1999) (Table
enhances the spontaneous release of acetylcholine (Ar- 3). Cleavage of SNAP-25 with botulinum neurotoxin A
gov and Yaari, 1979). Similarly, chlorpromazine in- (BoNT-A) prevents this enhancement. Thus, de-
creases in a dose-dependent manner the frequency of
sipramine acts by promoting spontaneous vesicular re-
mIPSCs in cultured rat hippocampal neurones
lease and not the passive leakage of glutamate
(Mozrzymas et al., 1999) (Table 3). The mechanisms
(Jabaudon et al., 1999) from presynaptic nerve termi-
underlying this action are not completely understood
nals. The enhancement of the mEPSC frequency is due
but seem to be partially Ca2 + -dependent. However,
to a desipramine-dependent activation of PKC and is
chlorpromazine still exerted its action in Ca2 + -free
independent of the desipramine-induced [Ca2 + ]i rise
solution suggesting that it directly acts on the secretory
apparatus (Mozrzymas et al., 1999). (Bouron and Chatton, 1999). Therefore, tricyclic an-
tidepressant drugs can activate the PLC-dependent sig-
3.6.2. Antidepressant drugs nalling pathway. Whether this action involves
Antidepressant drugs comprise a family of various GTP-binding proteins remains to be verified.
molecules. Their mechanisms of action are still debated.
Imipramine and its metabolite desipramine are struc- 3.6.3. Antiepileptic drugs
turally related to chlorpromazine. However, they be- Most of the clinically effective antiepileptic drugs
long to the family of tricyclic antidepressant drugs. appear to affect GABAergic transmission, Na+- or
Their pharmacological profile seems both different and Ca2 + -channel currents. Losigamone is a new anti-
complex. Acutely applied, tricyclic antidepressant drugs epileptic drug (Gasior et al., 1999). It modulates both
inhibit the uptake of monoamines but they also affect GABAergic and glutamatergic synaptic transmission.
many plasma membrane ion channels such as voltage- For instance, it increases the frequency of mIPSCs and
gated Na+-, Ca2 + -, or K+-channels (Isenberg and mEPSCs in a dose-dependent manner in cultured rat
Tamargo, 1985; Wooltorton and Mathie, 1993; Pan- hippocampal neurones (Draguhn et al., 1997) (Table 3).
crazio et al., 1998) and ligand-gated channels like nico- So far, its mechanism of action is not known.

Table 3
Modulation of spontaneous release in the hippocampus (see text for references)

Acting on Frequency of Mechanism of action

mEPSCs mIPSCs

Drugs of abuse
Cannabinoids CB1 o ?
Clinically used drugs
Antipsychotic drugs ? P Ca2+-independent
Antidepressant drugs ? P PKC-dependent Ca2+-independent
Antiepileptic drugs ? P P ?
Volatile anaesthetics ? U /
Organic nitrates ? P Ca2+-independent; SNAREs ?
Neurotrophins
BDNF TrkB receptors P P MAP kinase- and synapsin I-dependent
Hypoxia-ischemia
Ca2+-stores P Ca2+-dependent
A. Bouron / Progress in Neurobiology 63 (2001) 613635 625

3.6.4. Organic nitrates BDNF transiently elevated [Ca2 + ]i and suggested that
The organic nitrate nitroglycerine (NTG) is not only the release of Ca2 + from intracellular stores may di-
a redoubtable explosive but is also a powerful vasodila- rectly enhance spontaneous quantal release. However,
tor. It acts most likely by increasing the intracellular recent experiments do not support this latter hypothesis
nitric oxide (NO) production that leads to an enhanced (Jovanovic et al., 2000). By using synaptosomes purified
formation of cGMP. In cultured rat hippocampal au- from cerebral cortices they showed that presynaptic
tapses, NTG and nitrosocysteine, which generate nitro- BDNF receptors recruit TrkB and MAP kinase which
sonium ions, dramatically increase the rate of phosphorylates synapsin I. This report further under-
occurrence of mEPSCs (Pan et al., 1996) (Table 3). The lines the role of synapsins in controlling synaptic vesicles
NTG-dependent enhancement of the mEPSC frequency trafficking (Greengard et al., 1993) and demonstrates
is not due to a NTG-induced [Ca2 + ]i rise and is even that BDNF can stimulate neurotransmitter release via a
observed in Ca2 + -free solution. This suggests a Ca2 + -
MAP kinase-dependent signalling pathway.
independent mechanism of action (Pan et al., 1996).
NO-donors do not enhance the spontaneous quantal
3.8. Hypoxia-ischemia
release by affecting membrane fluidity but rather act by
directly modulating the secretory apparatus (Meffert et
Perfusing rat hippocampal slices with a normal exter-
al., 1996). Indeed, they promote the formation of a
nal saline saturated with 95% CO2 5% O2 instead of 5%
ternary SNARE complex by potentiating the binding of
SNAP-25 and VAMP/synaptobrevin to syntaxin 1a. CO2 95% O2 strongly increases the mEPSC frequency
They also inhibit the association of n-sec1 with syntaxin. within 1 min (Hershkowitz et al., 1993) (Table 3). This
The action of NO on the proteins involved in the hypoxia-dependent synaptic modulation is observed in
docking/fusion process is most likely due to a post- Ca2 + -free solution or with Cd2 + (Katchman and Her-
translational modification of sulfhydryl groups which, in shkowitz, 1993). Hypoxia is known to rapidly and
turn, affects synaptic protein-protein interactions (Mef- massively elevates [Ca2 + ]i (Silver and Erecinska, 1990).
fert et al., 1996). Dantrolen, which blocks Ca2 + release from caffeine-
sensitive stores, and caffeine, which depletes caffeine-
3.7. Neurotrophins sensitive stores, both prevent the hypoxia-induced
enhancement of mEPSC frequency. Therefore, the re-
Acute applications of either brain-derived growth lease of Ca2 + from caffeine-sensitive stores increases the
factor (BDNF) or neurotrophin factor-4/5 (NT-4/5) to spontaneous quantal release of glutamate (Katchman
embryonic or post-natal cultured rat hippocampal neu- and Hershkowitz, 1993). It is important to note that
rones transiently increase the frequency of miniature recent experiments performed under normoxic condi-
synaptic currents within 0.5 to 5 min (Lessmann et al., tions showed that the release of Ca2 + from caffeine-sen-
1994) (Table 3). Schindler et al., (2000) showed that sitive compartments increases the rate of occurrence of
BDNF up-regulates the spontaneous glutamate release TTX-resistant miniature GABAergic currents in neona-
irrespective of the phenotype of the target neuron (i.e. tal rat hippocampal neurones in culture (Savic and
excitatory or inhibitory). In contrast to Lessmann et al., Sciancalepore, 1999). All together, these results under-
(1994) and Li et al., (1998a), they found that the
line the importance of presynaptic Ca2 + stores in mod-
prolonged BDNF action has a slow onset of action
ulating neurotransmitter release. Katchman and
(Schindler et al., 2000). Using an adenovirus-mediated
Hershkowitz showed that various drugs could inhibit
gene transfer technique, Li et al. (1998b) selectively
the hypoxia-dependent spontaneous transmitter release.
expressed pre- or postsynaptically a truncated form of
the BDNF receptor (TrkB) which acts as a dominant For instance, agents that inhibit arachidonic acid forma-
negative. It inhibits the full-length TrkB response to tion and metabolism, NO synthase inhibitors, or
BDNF application. Presynaptic, but not postsynaptic, NMDA receptor antagonists, all prevent the hypoxia-in-
expression of TrkB prevents the BDNF-induced aug- duced potentiation of the TTX-resistant glutamatergic
mentation of the mEPSC frequency (Li et al., 1998b). release from CA1 pyramidal neurones (Katchman and
These experiments clearly demonstrate that activation of Hershkowitz, 1994, 1997). These results are in favour of
presynaptic BDNF receptors modulates the sponta- a postsynaptic locus of action and the production of a
neous quantal release. In the presence of K252a, a retrograde signalling messenger promoting the release of
tyrosine kinase inhibitor, BDNF does not modulate the Ca2 + from presynaptic nerve endings.
miniature current frequency (Li et al., 1998b). In addi-
tion, the neurotrophin-dependent modulation is par- 3.9. Neuropeptides
tially dependent on the external concentration of Ca2 +
since, in Ca2 + -free solution, the BDNF response was Opioid peptides are potent neuromodulators. In
attenuated. Li et al., (1998a) showed that applications of slices and organotypic slice cultures prepared from rat
626 A. Bouron / Progress in Neurobiology 63 (2001) 613635

Table 4
Modulation of spontaneous release in the hippocampus (see text for references)

Acting on Frequency of Mechanism of action

mEPSCs mIPSCs

Neuropeptides
Enkephalin m and d opioids receptors o PTX-sensitive G proteins, PKA-independent
Somatostatin SRIF1 receptors o PTX-sensitive- G proteins
Substance P PK1 U U /
NP Y NPY2 U /
TRH ? U /
VIP VIP1 P CAMP/PKA-dependant
Lipids
PAF ? P ?
Neurotoxins
BoNT/A SNAP-25 o o Reduced Ca2+-dependency?
BoNT/C Syntaxin, SNAP-25 o o
TeNT Synaptobrevin o o ?
a-LTx Latrophilin; Neurexin 1a P P Ca2+-independent ?, Synaptotagmin-1 dependent

hippocampi, activation of m- or d-opioid receptors somatostatin analogs, seglitide and octreotide, having
rapidly decreases the frequency of mIPSCs in CA1 and higher affinities for the SRIF1 subfamily of somatostatin
CA3 pyramidal neurones (Cohen et al., 1992; Capogna receptors than for the SRIF2 subfamily, mimic the
et al., 1993; Rekling, 1993; Lupica, 1995) (Table 4). neuropeptide action. A pre-treatment of the cells with
Removal of external Ca2 + or addition of Cd2 + does not PTX abolishes the somatostatin-dependent modulation
suppress the opioid receptor-dependent modulation of (Boehm and Betz, 1997). On the other hand, the
spontaneous quantal release (Capogna et al., 1993; thyrotropin-releasing hormone (TRH), the neuropeptide
Rekling, 1993). The signalling pathway linking these Y or substance P have no effect on the spontaneous
receptors to the secretory apparatus has not been TTX-resistant release of GABA and glutamate,
elucidated. respectively (Atzori and Nistri, 1996; McQuiston and
Vasoactive intestinal peptide (VIP) augments the Colmers, 1996; Kouznetsova and Nistri, 1998) (Table 4).
frequency of miniature GABAergic postsynaptic cur-
rents in cultured rat hippocampal neurones (Table 4). 3.10. Lipids
This effect is thought to involve VIP1 receptors of which
activation stimulates adenylate cyclase activity and Phospholipase A2 activity generates the biologically
cAMP production. Inhibition of the cAMP/PKA- active lipid platelet-activating factor (PAF). This medi-
dependent signalling pathway suppresses the VIP- ator is involved in many types of inflammation. It also
dependent modulation of the TTX-resistant spontaneous exerts a neuromodulatory action since PAF causes a
GABA release (Wang et al., 1997). Entry of Ca2 + strong augmentation of the mEPSC frequency in rat
through voltage-gated Ca2 + channels is not needed hippocampal neurones in primary cultures (Clark et al.,
because VIP enhances the mIPSC frequency even in the 1992; Kato and Zorumski, 1996) (Table 4). Its mecha-
presence of Cd2 + . GABA-activated Cl currents are not nisms of action are thus far not known.
modulated in the presence of VIP, indicating that the
peptide affects synaptic transmission in a PKA-depend- 3.11. Neurotoxins
ent manner by interfering at a step downstream to the
opening of presynaptic voltage-gated Ca2 + channels Tetanus and botulinum neurotoxins (TeNT; BoNT, 7
(Wang et al., 1997). serotypes: BoNT/A-G) are potent presynaptic in-
Somatostatin is another neuropeptide that has been hibitors of Ca2 + -evoked and spontaneous transmitter
shown to directly modulate, via presynaptic pertussis release. They inhibit exocytosis by cleaving their target
toxin-sensitive Gi/Go-coupled somatostatin receptors, SNARE proteins (Niemann et al., 1994; Humeau et al.,
the secretory apparatus and the spontaneous glutamate 2000). For instance, cleavage of SNARE proteins by
release (Boehm and Betz, 1997). Somatostatin decreases BoNT/A, BoNT/C, or TeNT strongly reduces the spon-
the frequency of mEPSCs in microisland cultures of rat taneous synaptic activity (Capogna et al., 1997) (Table
hippocampal neurones (Table 4). Like VIP, somatostatin 4). These toxins also abolish the potentiation produced
exerts its action even in the presence of Cd2 + . Two by various Ca2 + -dependent and Ca2 + -independent sec-
A. Bouron / Progress in Neurobiology 63 (2001) 613635 627

retagogues (Capogna et al., 1997). Increasing [Ca2 + ]o paired in hippocampal neurones from synaptotagmin-I
rescues the blockade produced by BoNT/A and BoNT/C deficient mice (Geppert et al., 1994). It could be hypoth-
but not by TeNT. Capogna (1998), concluded that esised that a-LTx receptor activation in CNS neurones
BoNT/A and BoNT/C change the Ca2 + -dependency of and PC12 cells recruits different target proteins.
the release process.
a-LTx is a component of black wider spider venom. 3.12. Miscellaneous
It causes massive release from endocrine and neuronal
cells (Henkel and Sankaranarayana, 1999). Studies aim-
ing at elucidating its mechanisms of action led to 3.12.1. Cyclothiazide
conflicting results with regard to the role of Ca2 + . In This compound is a benzothiadiazide that blocks
CA3 pyramidal neurones, low concentrations (B 0.5 AMPA receptor desensitization (Yamada and Tang,
nM) of a-LTx cause a strong enhancement of the 1993). Therefore, it is a postsynaptic neuromodulator
frequency of mIPSCs and mEPSCs (Capogna et al., that affects the kinetics of AMPA receptor currents and
1996a) (Table 4). This effect occurs even in the presence the amplitude of mEPSCs. However, cyclothiazide in-
of Cd2 + or with a nominally Ca2 + -free/EGTA external creases the frequency of mEPSCs (Yamada and Tang,
solution but requires Munc-13, a presynaptic phorbol 1993) (Table 5). This potentiation is not due to a
ester receptor involved in the maturation process of SVs cyclothiazide-dependent enhancement of the mEPSC
(Augustin et al., 1999) (see Section 3.3.1). Gd3 + slightly amplitude that would favor the detection of miniature
reduces the a-LTx-dependent augmentation of the fre- postsynaptic currents that are below the detection
quency of miniature postsynaptic currents, probably threshold in the absence of cyclothiazide. Rather, it
because the cation interferes with a a-LTx binding site reflects a real presynaptic modulation (Diamond and
(Capogna et al., 1996b). Cleavage of synaptobrevin with Jahr, 1995). The cyclothiadiazide-dependent enhance-
BoNT-F abolishes a-LTx action, indicating the vesicular ment of glutamate release occurs even without external
origin of the neurotransmitter (Capogna et al., 1996a). Ca2 + . Its presynaptic mechanism of action is not known.
Two structurally unrelated a-LTx receptors have been
identified, neurexin 1a and latrophilin, a G-protein 3.12.2. Hypertonic solutions
coupled receptor stimulating PLC activity. a-LTx binds Application of hypertonic solutions strongly increases
to neurexin 1a in the presence of external Ca2 + whereas spontaneous synaptic activity (Bekkers and Stevens,
Ca2 + ions are not needed for the a-LTx binding to 1989) (Table 5). A detailed molecular description of this
latrophilin. a-LTx receptors are thought to directly modulation is still lacking. Hypertonic solutions proba-
interact with the secretory apparatus of nerve terminals. bly act in a Ca2 + -independent manner since spontaneous
However, the experiments aimed at identifying the presy- release is also enhanced in hippocampal neurones defi-
naptic proteins stimulated in response to neurexin 1a cient in synaptotagmin-I, the putative Ca2 + -sensor
activation have led to conflicting results. For instance, in (Geppert et al., 1994).
PC12 cells deficient in synaptotagmin-I, the putative
Ca2 + sensor mediating Ca2 + -evoked neurotransmission 3.12.3. Bafilomycin A1
(Sudhof and Rizo, 1996), a-LTx fails to elicit nore- It is a vesicular adenosine 5-trisphosphate (ATP)ase
pinephrine release (Shoji-Kasai et al., 1994). On the other inhibitor that decreases the filling state of SVs. But it also
hand, the a-LTx-dependent glutamate release is unim- seems to directly interfere with the secretory ap-

Table 5
Modulation of spontaneous release in the hippocampus (see text for references)

Acting on Frequency of Mechanism of action

mEPSCs mIPSCs

Miscellaneous
Cyclothiazide AMPA receptors P Ca2+-independent
Hypertonic medium ? P P Ca2+-independent
Bafilomycin A1 Vesicular ATPase o ?
VX, paraoxon P P Ca2+-dependent
N-ethylmaleimide NSF P Ca2+-independent
Immunoglobulins ? P Ca2+-independent
Ca2+-ionophores P Ca2+-dependent
pH ? P Ca2+-dependent via the Na+/Ca2+ exchanger
Caffeine Ryanodine receptors P Ca2+-dependent
Thapsigargin Ca2+ pumps P Ca2+-dependent
628 A. Bouron / Progress in Neurobiology 63 (2001) 613635

paratus. For example, it potently decreases the bath-perfusing medium is switched to a Ca2 + -free/
frequency of mEPSCs in hippocampal cultured EGTA solution. Therefore, ionomycin stimulates the
neurones (Araque et al., 2000) (Table 5). Its spontaneous release of GABA and glutamate by pro-
mechanisms of action is currently unknown. However, moting Ca2 + influx through a Cd2 + -insensitive entry
as already suggested (Golan and Grossman, 1996; pathway. By using BoNT-F that selectively cleaves the
McLachlan, 1975; Pothos et al., 1998; Poulain et al., SNARE protein VAMP/synaptobrevin, Capogna and
1986; Sacchi and Perri, 1973; Tian et al., 1999), the colleagues (1996a) showed that the ionomycin-depen-
neurotransmitter content of SVs could influence the dent transmitter release is of vesicular origin since
probability of release. BoNT-F abolishes the ionomycin response. In microis-
lands of cultured hippocampal neurones from mice,
3.12.4. Organophosphorus compounds calcimycin, another Ca2 + ionophore, increases the rate
VX is an organophosphate agent similar to sarin. of spontaneous glutamate release. This effect disap-
Both are powerful inhibitors of acetylcholinesterases pears in Munc-13-deficient mice (Augustin et al., 1999)
and thus increase the concentration of acetylcholine. (see Section 3.3.1) (Table 5).
VX stimulates spontaneous quantal release of GABA
and glutamate in cultured hippocampal neurones 3.12.8. pH
(Rocha et al., 1999) (Table 5). Its mechanism of action Intracellular acidification with the weak acid propi-
is Ca2 + -dependent and not related to the inhibition of onate transiently elevates the mEPSC frequency in
acetylcholinesterase. In contrast to VX, sarin does not pyramidal cells in culture (Trudeau et al., 1999) (Table
change the frequency of mEPSCs or mIPSCs (Chebado 5). The mechanism of action involved is not known.
et al., 1999). Paraoxon, the metabolite of parathion, a Upon washout, there is a strong augmentation of the
commonly used insecticide, is another anti- mEPSC frequency which is due to the entry of Ca2 +
cholinesterase drug that can cause poisoning in man. It through the Na+/Ca2 + exchanger (Trudeau et al.,
1999) (see Section 3.2.1.1).
augments the frequency of miniature postsynaptic cur-
rents (Rocha et al., 1996). The mechanisms of action of
these agents are currently unknown.
4. Presynaptic facilitation
3.12.5. N-ethylmaleimide
Neuromodulators can enhance the action potential-
The sulphydryl reagent N-ethylmaleimide (NEM)
independent neurotransmitter release by increasing
blocks membrane fusion by inhibiting the ATP-binding
[Ca2 + ]i nearby release sites. A number of different
protein NSF, an NEM-sensitive factor (Rothman,
mechanisms can cause a rise in intra-terminal Ca2 + : (1)
1994). Recordings from CA1 pyramidal neurones in
Ca2 + entry through the plasma membrane (e.g. via
slices showed that NEM strongly elevates the frequency
presynaptic nicotinic receptors or the Na+/Ca2 + ex-
of mIPSCs (Morishita et al., 1997) (Table 5). It most
changer; Ca2 + ionophores); (2) the release of Ca2 +
likely acts in a Ca2 + -independent manner since this from internal compartments (caffeine-, IP3-sensitive
upregulation develops even when the bath solution Ca2 + stores; mitochondria). However, the filling state
contains no Ca2 + and 100 mM EGTA (Morishita et al., of Ca2 + stores may critically influence the effect of
1997). So far, the molecular mechanisms underlying Ca2 + -mobilising drugs on synaptic transmission. Gen-
NEM action are not understood. erally, Ca2 + triggers a rapid and short lasting enhance-
ment of the miniature frequency. Synapses release
3.12.6. Immunoglobulins (IgGs) neurotransmitters spontaneously or after the arrival of
Andjus et al., (1997) showed that focal applications an action potential. Several reports showed that these
of IgGs from amyotrophic lateral sclerosis (ALS) pa- two modes of release do not recruit the same presynap-
tients to hippocampal neurones in culture increase the tic proteins. For instance, at the Drosophila neuromus-
frequency of mEPSCs (Table 5). IgGs do not promote cular junction, evoked responses disappear in
the release of glutamate by triggering Ca2 + influx into synaptobrevin-deficient embryos whereas the sponta-
presynaptic terminals since the effect develops in the neous release still occurs (Deitcher et al., 1998). In the
presence of a nominally Ca2 + -free external solution hippocampus, mutation of the synaptotagmin-I gene
(Andjus et al., 1997). The signalling cascade linking the does not affect the mEPSC frequency but abolishes
uncharacterized IgG targets and the secretory appara- Ca2 + -dependent responses (Geppert et al., 1994). It is
tus is not known. likely that Ca2 + -dependent secretagogues promote the
action potential-independent release via a synaptotag-
3.12.7. Ca 2 + ionophores min-dependent mechanism.
Ionomycin increases spontaneous synaptic activity Secretagogues can modulate synaptic transmission by
(Capogna et al., 1996b). This effect occurs even in the modifying the phosphorylation/dephosphorylation state
presence of Cd2 + but is completely reversed when the of presynaptic proteins. M1/M5 muscarinic, D1 do-
A. Bouron / Progress in Neurobiology 63 (2001) 613635 629

pamine and BDNF receptors as well as tricyclic antide- mechanisms activated by excitatory neurotransmitters.
pressant drugs or the neuropeptide VIP facilitate spon- Beside BoNTs and TeNT where the target proteins
taneous exocytosis by activating protein kinases. PKA have been clearly identified, the signalling messengers
and PKC have been implicated in various examples of recruited by the inhibitory neuromodulators remain to
presynaptic plasticity but MAP kinase can also affect be understood. For instance, the coupling mechanism
the basal release (Jovanovic et al., 2000). It remains to linking adenosine A1 receptors and the secretory ap-
be seen whether other protein kinases of the presynap- paratus is still unclear (Bouron, 1999). With respect to
tic element have similar properties. In addition, several the other inhibitory neuromodulators, the kainate-de-
important issues remain unresolved: the identity of the pendent mechanism of action is among the best charac-
kinase isoforms recruited, as well as their targets and terized. Activated presynaptic kainate receptors
the mechanism by which phosphorylated proteins facili- stimulate PLC and PKC activity. This represents the
tate the fusion of SVs with the plasma membrane. In only example where PKC activation depresses synaptic
the case of the BDNF-dependent modulation, a recent transmission in the hippocampus.
study identified synapsin I as a putative downstream
signalling molecule (Jovanovic et al., 2000).
Both PKC and PKA increase the probability of 6. Conclusion
release by increasing the size of the readily releasable
pool of synaptic vesicles (Stevens and Sullivan, 1998; The rate of spontaneous release is not constant. It
Lonart and Sudhof, 1998). There is a positive correla- can be up- or down-regulated by various means such as
tion between the size of the nerve terminal and the the electrical activity of the neuron, neurotransmitters,
number of vesicles (Dobrunz and Stevens, 1997; neuropeptides, cations, neurotoxins, lipids, neuro-
Schikorski and Stevens, 1997). In addition, the rate of trophic factors, clinically used drugs, hypertonic solu-
spontaneous miniature postsynaptic currents depends tions, immunoglobulins . The physiological
on the size of the vesicle pool (Prange and Murthy, significance of this modulation is not well understood
1999). Therefore, neuromodulators could alter the size although action potential-independent release plays a
of presynaptic nerve endings by regulating the size of trophic role since BoNT-dependent inhibition of exocy-
the readily releasable pool. PKA activation also aug- tosis causes the loss of dendritic spines (McKinney et
ments the number of release sites but this effect has a al., 1999). Inhibitory neuromodulators that produce a
slow onset of action and depends on proteins synthesis long lasting depression of spontaneous release could
(Ma et al., 1999). Another putative mechanism is the also alter the length of spines. For instance, a long-term
rapid recruitment of previously silent release sites as treatment (1 day) with estradiol reduces mIPSC fre-
shown for PKA in the cerebellum (Chavis et al., 1998). quency, increases mEPSC frequency (Murphy et al.,
A third group of secretagogues is composed of neu- 1998) and increases dendritic spine density (Murphy
romodulators that do not stimulate protein kinases and and Segal, 1996; Murphy et al., 1998). Recent experi-
promote the release in a Ca2 + -independent manner ments suggest that most of the dendritic hippocampal
(e.g. ruthenium red, hypertonic solutions, bafilomycin, Ca2 + signal, in response to synaptically released neuro-
NEM, cyclothiazide, ). Their mechanism of action is transmitters, is mainly due to the mobilisation of Ca2 +
still completely unknown. In the case of NO-donors, from internal stores (Svoboda and Mainen, 1999). The
they promote the formation of a ternary SNARE com- release of Ca2 + from these compartments alters the
plex. Whether other secretagogues can directly modify morphology of dendritic spines (Korkotian and Segal,
the proteins involved in the exocytosis remains to be 1999). It could be proposed that spontaneously exocy-
determined. tosed neurotransmitters trigger spontaneous Ca2 + tran-
sients (Murthy et al., 2000) which, in turn, affect spine
morphology. However, this simple scheme explaining
5. Presynaptic inhibition the trophic role played by the Ca2 + -independent re-
lease is only valid for excitatory synapses. The sponta-
LTD induction protocols, neurotoxins (BoNTs, neous release does not seem to be involved in the
TeNT), activation of some neurotransmitter receptors formation of synapses (Gomperts et al., 2000; Verhage
(adenosine A1, GABAB, mGluRIIs, kainate, and his- et al., 2000) but contributes to the maintenance of the
tamine receptors) as well as activation of neuropeptide dendritic structures (McKinney et al., 1999). Therefore,
(opioids) or cannabinoid (CB1) receptors rapidly de- by controlling the density and/or the length of dendritic
press spontaneous synaptic activity. In each instance, spines, the action potential-independent release could
neurotransmitter release is inhibited in a Ca2 + -indepen- then influence information processing. In addition, as
dent manner. The signalling pathway linking the in- already discussed by Staley (1999), the basal release
hibitory neurotransmitter receptors and the secretory may also carry synaptic information. For instance,
apparatus is even less understood than the coupling Lowen et al. (1997) suggested that the spontaneous
630 A. Bouron / Progress in Neurobiology 63 (2001) 613635

vesicular release is not a memoryless stochastic process. Berridge, M.J., 1998. Neuronal calcium signaling. Neuron 21, 1326.
In conclusion, the physiological significance of the ac- Betz, A., Ashery, U., Rickmann, M., Augustin, I., Neher, E., Suhdof,
T.C., Rettig, J., Brose, N., 1998. Munc-13-1 is a presynaptic
tion potential-independent neurotransmitter release as phorbol ester receptor that enhances neurotransmitter release.
well as the mechanisms of its modulation remains to be Neuron 21, 123 136.
clearly understood. Blaustein, M.P., Lederer, W.J., 1999. Sodium/calcium exchange: its
physiological implications. Physiol. Rev. 79, 763 854.
Boehm, S., 1999. Presynaptic a2-adrenoceptors control excitatory,
but not inhibitory, transmission at rat hippocampal synapses. J.
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