Neuronal Plasticity and Mood Disorders


Recent evidence suggests that reorganization of neuronal connectivity might play an important role in the pathophysiology of mood disorders and in both pharmacological and psychological treatments of depression. This evidence suggests a new framework for the etiology of mood disorders that focuses more on the problems in neuronal connectivity, plasticity and information processing in the brain than on abnormalities in chemical neurotransmission. Although this framework is still controversial and far from being complete, improved familiarity with the concepts of neuronal development and activity-dependent plasticity among mental health professionals would be useful.

Psychiatric Times

October 2005


Issue 11

The ability to adapt to changing environmental conditions is the most fundamental feature of the nervous system. At the neurobiological level, this adaptation corresponds to neuronal plasticity, defined as the lifelong ability of the brain to reorganize neural pathways based on new experiences. Reorganization is robust during early postnatal development and declines thereafter, but experiences shape neuronal networks to a more limited extent in the adult brain as well (Berardi et al., 2000). Plasticity may involve neurogenesis and neuronal death, formation or pruning of neuronal connections, or changes in the strength of existing connections. Data from the last decade have suggested that abnormalities in the development and information processing in the neuronal networks involved in emotional processes may at least partially underlie mood disorders (Castrén, 2005; Charney and Manji, 2004; Duman et al., 1997; Nestler et al., 2002). Therefore, plasticity of neuronal networks may be a necessary component in successful antidepressant treatments, including pharmacological and psychological therapies. Introduced here will be the principles of neuronal development and activity-dependent neuronal plasticity. The recent data suggesting the role of these processes in mood disorders and antidepressant action will be reviewed. Evidence supporting and contradicting the role of neuronal plasticity in depression has recently been reviewed elsewhere (Castrén, 2005).

Information in the brain is believed to be encoded in vast and overlapping networks of interconnected neurons. Since there are more neurons in the brain than there are DNA base pairs in the human genome, and each neuron makes a connection with hundreds of other neurons, it is obvious that the genomic information cannot code for more than a basic layout of neuronal connections in the brain. The fine-tuning of neuronal connectivity is achieved through neuronal plasticity, a process that depends on neuronal activity and environmental experiences (Katz and Shatz, 1996).

The Figure depicts the steps in the formation and refinement of neuronal networks. (Due to copyright concerns, the Figure cannot be reproduced online. Please see p44 of the print edition--Ed.) Network formation begins with "trial contacts" between individual neurons (Figure, top panel a) (Hua and Smith, 2004). These initial contacts are mainly thought to be formed stochastically, though it is probable that they are to some extent guided by genetic information. The fate of these trial contacts depends on how effectively they mediate relevant information. Active neurons release a neurotransmitter that, in turn, stimulates the release of a neurotrophic factor from the postsynaptic side (Figure, middle panel a). The bidirectional "discussion" over the synapse mediated by the neurotransmitter and neurotrophic factor leads to the stabilization of an active synapse, whereas inactive trial synapses, which cannot stimulate the release of the neurotrophic factor, get pruned away (Figure, lower panel a). In this way, those contacts that best mediate information get stabilized as new synapses (Cohen-Cory, 2002; Hua and Smith, 2004). Therefore, the connectivity and shape of a dendritic tree of an individual neuron are not determined genetically, but form in interaction with the environment, exactly as the branching and outline of a tree is shaped by the availability of light.

If two neurons innervate the same target neuron and are active at the same time (Figure, middle panel b), they can cooperate and get stabilized with a level of activity that is lower than that required for a single neuron, whereas neurons active off-beat are weakened and eliminated (Figure, lower panel b) (Poo, 2001; Thoenen, 1995). This is the basis for the formation of networks of coherently active neurons: "Neurons that fire together, wire together" (Katz and Shatz, 1996). Since neuronal activity reflects environmental stimuli, the activity-dependent neuronal plasticity gradually tunes the networks to optimally code for environmental information.

The critical process is not the formation of neurons or synaptic connections, which are made in excess, but the selection of the useful neurons and connections and the elimination of inactive ones, a process that optimizes signal-to-noise ratio. This could be likened to tuning a radio: Increasing volume (production of more neurons or synapses) does not help if the radio is tuned between stations, but optimal tuning (stabilization of active synapses and elimination of inactive ones) makes the broadcast intelligible even at low volume.

A well-characterized example of an activity-dependent network formation is the development of cortical maps in the sensory cortical areas to reflect their environmental input (Katz and Shatz, 1996). For example, if one of the eyes is covered during a critical period of postnatal development, the projections originating from this eye are inactive and get pruned in the visual cortex, which gradually gets almost exclusively innervated by connections originating from the open, active eye. If the covered eye is not opened before the end of the critical period, the dominance of the open eye gets stabilized and the covered eye remains amblyopic, even if it is opened in adulthood.

Although the majority of information that we have on brain development comes from sensory systems, there is evidence to suggest that a similar competition-based organization takes place in the development of other neural systems, including those involved in social interaction. However, very little is known about the organizing principles and the brain regions involved. One important clue comes from the role of serotonin in the developing brain. Genetic elimination of the 5-HT1A receptor in mice produces anxiety-type behavior in adults, but only when the receptor is absent during early postnatal development; when it is functioning normally during development but absent in adulthood, no behavioral effects can be observed (Gross et al., 2002). Increasing extracellular serotonin levels by genetic manipulation or antidepressant drug treatment during a critical postnatal period disrupts the organization of cortical sensory maps in rodents (Gaspar et al., 2003; Xu et al., 2004). Parallel to the disturbances in sensory cortical map formation, these same treatments, when given during the first weeks of life, produce an apparently permanent behavioral phenotype, which has been used as a model for depression (Ansorge et al., 2004; Feng et al., 2001). Interestingly, the behavioral pattern produced by these early genetic or pharmacological manipulations resembles the pattern observed in rats that experience stress or reduced maternal care during the early postnatal period (Meaney, 2001; Mirescu et al., 2004).

These data raise the possibility that social interactions such as maternal care are required during early postnatal development to organize neuronal connectivity in a similar manner as described for the developing sensory systems, and that genetic defects or adverse environmental effects may predispose to mood disorders in adulthood by disturbing the organization of this cortical map during a developmental critical period. This view is supported by recent observations that hippocampal volume was reduced in those depressed patients who had experienced early social trauma but not in depressed patients without early adverse experiences (Vythilingam et al., 2002).

Stress in adulthood also influences neuronal plasticity (McEwen, 2001). In experimental animals, stress reduces hippocampal volume and production of new neurons, and it produces atrophic changes and compromised synaptic transmission in critical neuronal pathways in hippocampus (Czeh et al., 2001). Similarly, imaging studies in patients with depression have revealed reductions in gray matter volume in the prefrontal cortex and the hippocampus (Drevets, 2001; Sheline, 2003). At least part of these morphological alterations seems to be reversible by antidepressant therapies (Czeh et al., 2001; Drevets, 2001). As the neuronal processes and synapses take up most of the space in the gray matter, reduced volume suggests reduced neuronal complexity and connectivity. Furthermore, stress reduces levels of brain-derived neurotrophic factor (BDNF) (Smith et al., 1995), which is a prominent mediator of neuronal plasticity in both the developing and adult brain (Lu, 2003; Thoenen, 1995). These data suggest that both early postnatal and adult stress reduce the capacity of the brain to take advantage of neuronal plasticity.

Antidepressant drug treatment has been found to induce plasticity-type responses in several cortical regions, particularly the hippocampus (Castrén, 2004). New neurons are born in the dentate gyrus throughout life and environmental stimuli regulate hippocampal neurogenesis: Enriched environment increases neurogenesis whereas stress decreases it (McEwen, 2001; van Praag et al., 2000). Interestingly, maternal separation during early life produces a long-term reduction in neurogenesis still observed in adults (Mirescu et al., 2004). Antidepressants have been shown to increase neurogenesis when administered over a sufficiently long period (Castrén, 2004; Malberg et al., 2000). Importantly, if neurogenesis is prevented, antidepressants fail to produce typical behavioral responses in rodents, demonstrating at least an association between neurogenesis and behavioral effects on antidepressants (Santarelli et al., 2003). The increased neurogenesis produced by antidepressants was accompanied by a simultaneous increase in neuronal elimination in the mouse dentate gyrus, indicating that antidepressants increase the turnover of neurons in the hippocampus rather than just neurogenesis (Sairanen et al., 2005). This suggests that enhanced neurogenesis induced by antidepressants increases competition between neurons for the ability to best innervate their targets in the hippocampus, in an analogous manner as described in the Figure. Together these data demonstrate that antidepressants enhance neuronal plasticity in the hippocampus in a manner that is analogous to that produced by favorable environmental stimulation (van Praag et al., 2000).

Antidepressants enhance the production and signaling of BDNF (Altar, 1999; Castrén, 2004). Injection of BDNF into the brain (Shirayama et al., 2002; Siuciak et al., 1997) or genetic enhancement of BDNF signaling (Koponen et al., in press) produces similar behavioral responses in rodents as antidepressants do, and the inhibition of BDNF release or signaling prevents these behavioral effects (Saarelainen et al., 2003). Therefore, BDNF signaling appears both necessary and sufficient for antidepressant-induced behavioral responses. It is important to emphasize that BDNF expression or its concentration are not the central points here, but the role of BDNF in the selection between active and inactive connections in networks (Figure). Interestingly, a polymorphism in the BDNF gene that influences activity-dependent BDNF release is associated with familial mood disorder in humans (Neves-Pereira et al., 2002; Sklar et al., 2002), which indicates that plasticity of neuronal networks is of importance in the development of mood disorders.

These data suggest a novel concept in the mechanism of action of antidepressant drugs and the pathophysiology of depression. The drugs stimulate processes that are critically involved in the activity-dependent shaping of neuronal connectivity in developing brains, and there is increasing evidence to suggest that these gradual effects on neuronal networks, rather than changes in chemical balance in brains alone, underlie the beneficial therapeutic effects of these drugs (Castrén, 2005; Charney and Manji, 2004; Duman et al., 1997; Nestler et al., 2002). The fact that environmental stimuli and antidepressants bring about similar effects on neurotrophins and neurogenesis suggests that behavioral therapy and antidepressants might both impinge on the same neuronal mechanism: the activity-dependent neuronal plasticity (Castrén, 2005). Hence, it is to be expected that drug treatment and talk therapies might act synergistically when used in combination, and there is evidence to support this idea (March et al., 2004).

It is also conceivable that some patients might continuously require the plasticity-supporting effects of antidepressant drugs to maintain the connectivity of critical networks; these patients need lifetime maintenance treatment and easily relapse if the treatment is terminated or changed to placebo. Although it is unclear how much time reorganization of neural networks takes in the human brain, a requirement for such gradual changes might underlie the fact that essentially all treatments of mood disorders, including pharmacological and psychological therapies and electroconvulsive shock treatment, typically take several days to weeks to bring about clinical effects.

Although these new views are still preliminary and partially controversial (Castrén, 2005), they suggest that it is important for scientists and practicing psychiatrists to become familiar with the principles of developmental neurobiology, neuronal plasticity, and their implication on normal mood and mood disorders.


The author would like to thank the members of his lab for discussions and comments. The original work in his laboratory, which is the foundation of this review, has been supported by the Sigrid Juselius Foundation, the Academy of Finland, Sohlberg Foundation and GlaxoSmithKline.

Dr. Castrén is Sigrid Juselius Professor of Neuroscience at the University of Helsinki's Neuroscience Center in Helsinki, Finland.


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