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TRKB
TRKB
might be preceded by, functional deficits,
P P
such as memory impairment35. As the neu-
↑Ca2+ ronal processes and synapses take up most of
Lithium GR the space in the grey matter, reduced volume
might mean reduced neuronal complexity
AKT GSK3 ROS ↓Energy and connectivity. To at least some degree,
capacity
these morphological alterations seem to be
P
reversible by antidepressant therapies34,40.
BDNF
BAD TRKB
Neuroplasticity and
BCL-X cellular resilience TRKB The results of a recent study show that
P reduced hippocampal volume is particularly
ROS
Ca2+
common in patients with depression who
BCL2 Ras GTP suffered a childhood trauma41, which indi-
Cytocrome c
Mitochondrion cates that severe stress during a critical devel-
_ CREB RAF opmental period might have lasting effects
BCL2 on the morphology of the brain. These data
Lithium RSK2 MEK support the hypothesis that mood disorders
are associated with compromised informa-
Lithium VPA Failure of
ERK tion processing in crucial neural networks,
neuroplasticity and that the action of antidepressants might
signal result in morphological and physiological
reorganization of specific neuronal connec-
tions in the brain. Furthermore, imaging and
genetic studies are beginning to elucidate
Genetic and Repeated episodes Cerebrovascular
developmental factors illness progression insufficiency which neural structures are involved in differ-
Figure 2 | The chemical hypothesis of depression. The intracellular pathways that are affected by
ent mental health disorders and which circuits
mood disorders and antidepressants. AKT, protein kinase B; BAD, BLC-associated death promoter; might be important targets for successful
BCL2, B-cell leukaemia/lymphoma 2; BCL-X, BCL2-like protein 1; BDNF, brain-derived neurotrophic medications6.
factor; CREB, cyclic AMP responsive element binding protein; ERK, mitogen activated protein Perhaps the most important evidence for
kinase 1; GR, glucocorticoid receptor; GSK3, glycogen synthase kinase 3; MEK, ERK kinase; the network hypothesis is the recent obser-
VPA, valproate; NA, noradrenaline; P, phosphate; RAF, RAF proto-oncogene; ROS, reactive oxygen vation that antidepressants increase the
species; Ras GTP, Ras GTPase-activating protein; RSK2, ribosomal protien S6 kinase polypeptide 3;
production of new neurons in the rodent
TRKB, neurotrophic tyrosine kinase receptor type B; 5-HT, 5-hydroxytryptamine (serotonin).
Adapted, with permission, from REF. 6 © (2001) Macmillan Magazines Ltd. hippocampus42. Importantly, the increased
neurogenesis that is brought about by
chronic antidepressant treatment correlates
with the behavioural effects produced by
Monoamines, particularly serotonin, It is well known that the plasticity of neural antidepressants43. Newly generated neurons
have a significant role during brain develop- connectivity in the brain is greater and more differentiate over time, and are only mature
ment23. Genetic elimination of the 5-HT1A extensive during critical periods of postnatal enough to participate in information
receptor produces anxiety-type behaviour in development than in adults, and that func- processing several weeks after their birth44.
adult mice, but only when the receptor was tional structures that are formed during The fact that this time course correlates with
absent during early postnatal development critical periods remain relatively stable in the delayed onset of the clinical effects of
— its absence in adulthood produces no adulthood31 (BOX 1). These data highlight the antidepressants has created a lot of excite-
behavioural effects24. Furthermore, muta- effects that serotonin and antidepressant ment among neuropharmacologists. In the
tions in monoamine oxidase A produce treatments have on the plasticity of neural hippocampi of rodents that have received
behavioural alterations in both men and networks, and link the effects of antidepres- antidepressant treatment, the elimination of
mice25,26, and disrupt the developmental sants with the environmental manipulations neurons through apoptotic cell death
organization of thalamocortical inputs and that are known to modulate neural network increases simultaneously with increased
cortical modules in the brains of rodents23,27. formation during development31. Moreover, neurogenesis, which indicates that antide-
A similar disruption in thalamocortical they indicate that the effects of the drugs pressants might increase neuronal turnover
organization has also been produced with might be more robust in the brain during rather than neurogenesis per se 45. This effect
the administration of antidepressants and early postnatal development and qualita- might be functionally analogous to the
monoamine oxidase inhibitors during early tively different when compared with the overproduction of neurons that occurs
postnatal development27,28. Furthermore, effects seen in the adult brain, which could during the development of the peripheral
antidepressant treatment during early post- have significant implications for the pre- nervous system (BOX 1), and indicates that
natal life can produce permanent behav- scription of antidepressants to children and antidepressants might facilitate optimiza-
ioural disturbances in adult animals 29,30. pregnant mothers. tion of neuronal connectivity by increasing
Box 1 | Activity-dependent refinement of neural networks be expected to be more beneficial than either
treatment alone, and there is evidence that
During the development of the peripheral nervous system, neurons are produced in excess this might be the case59. As the network
and compete to innervate the target tissues61. Neurotrophic factors, which are secreted by hypothesis emphasizes the importance of
the target tissues (for example, muscles) in limited quantities, and which are required by environmental information in the process of
innervating neurons for their survival, select from the competing neurons those that best activity-dependent selection of neurons and
innervate the target, and the defeated neurons are eliminated by apoptosis. This competitive synapses (BOX 1), it predicts that full recovery
process matches the number of neurons and targets and ensures optimal innervation of the would not even be possible with drug treat-
target cells61–63. In the CNS, neurons target other neurons and competitive selection takes
ment alone, but that external stimuli, such as
place at several levels: among neurons (as in the peripheral nervous system), among axon
social communication, would be required to
branches and among synaptic contacts64. In the brain, the release of target-derived trophic
provide environmental input for the selec-
factors is activity dependent: the innervating neuron must sufficiently stimulate the target
neuron in order to induce the production and release of the trophic factor50,51. Neurons can
tion of the appropriate network connections
(FIG. 3). The role of environmental stimula-
also cooperate to increase the release of trophic factors: simultaneously active neurons that
innervate the same target neuron can induce the release of trophic factors through a much tion might also be related to the fact that
lower level of activity than is required for a single innervating neuron51. This activity- major depression is typically cyclical and
dependent cooperative selection of simultaneously active neurons and the elimination of often self-limiting, and many patients
inactive and incoherent contacts is considered to be crucial in the development of large, improve with time even in the absence of
coherently active neural networks: ‘the neurons that fire together, wire together’21. Through active treatment.
these mechanisms, neuronal structure and neurotransmission are optimized to best store Finally, the effects of antidepressant drugs
and process relevant information. During critical periods in early postnatal development, on network plasticity in the brain might
much larger changes in the connectivity and organization of neural networks take place explain why they are effective for many
than is possible in the adult brain31. Nevertheless, even the adult brain still shows significant neuropsychiatric disorders, including anxiety,
plasticity. The crucial event in activity-dependent plasticity is not the formation of neuronal obsessive-compulsive disorder, eating dis-
contacts (which might occur stochastically and in excess) but the activity-dependent orders, chronic pain and tinnitus. It has been
selection and stabilization of those synapses that mediate useful signals, together with the proposed that some of these disorders, par-
selective pruning and elimination of those that produce random noise20. Therefore, ticularly chronic pain, might be produced by
neurogenesis and synaptogenesis cannot simply be considered beneficial, and neuronal aberrant neuronal connectivity 60.
death and synapse elimination harmful; what matters is the optimization of the The hypothesis that mood represents a
signal–to–noise ratio in the network. Neurotrophins are important in this process through functional state of neural networks might
their selective release from active connections; indiscriminate increases in the levels of
sound incompatible with the efforts of ratio-
neurotrophic factors or their signalling (as, for example, would be produced by a
nal drug development. However, the data
neurotrophic factor receptor agonist) is not expected to be beneficial to the network, as both
reviewed above indicate that the antidepres-
active and inactive connections would be similarly supported.
sant drugs that have been used successfully
for several decades might function by initi-
ating such plastic processes, apparently
Future perspectives plasticity. Therefore, psychological and indirectly, by influencing monoamine
The view of mood disorders as problems of pharmacological therapies, electroconvulsive metabolism. It is possible that a similar
information processing in the brain has shock treatment and placebo effects might all process could also be initiated through
several important implications. As devel- lead to improved information processing and other pharmacological mechanisms, which
opmental neurobiologists have been investi- mood recovery through mechanisms that ini- might become the targets of new anti-
gating activity-dependent plastic processes tiate similar processes of plasticity (FIG. 4). In depressants that could help patients who are
for decades, collaboration between neuro- this scenario, a combination of drug treat- resistant to current drugs and only respond
pharmacologists, developmental neuro- ment and psychological rehabilitation would to electroconvulsive shock treatment.
scientists and behavioural geneticists should
be encouraged. Recent studies clearly show
that genetic manipulation of neural circuits
and assessment of the consequences through Pharmacotherapy
in vivo recording techniques and behav-
Acitivity-dependent plasticity
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seizures: induction of neurotrophic and angiogenic 44. van Praag, H. et al. Functional neurogenesis in the adult http://www.helsinki.fi/neurosci/castren.htm
factors. J. Neurosci. 23, 10841–10851 (2003). hippocampus. Nature 415, 1030–1034 (2002). Access to this interactive links box is free online.