Department of Psychiatry, University of Dundee, Dundee
Correspondence: Professor Ian C. Reid, Department of Psychiatry, University of Dundee, Ninewells Hospital, Dundee DDI 9SY
Declaration of interest Our laboratory has received research funding from Organon Laboratories and Wyeth UK.
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ABSTRACT |
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Aims To relate recent findings from the basic neurosciences to the pathophysiology of depressive disorder.
Method Drawing together findings from molecular and physiological studies in rats, social studies in primates and neuropsychological studies in humans, we review the neurotrophic and neuroplastic effects of antidepressants and stress.
Results Stress and antidepressants have reciprocal actions on neuronal growth and vulnerability (mediated by the expression of neurotrophins) and synaptic plasticity (mediated by excitatory amino acid neurotransmission) in the hippocampus and other brain structures. Stressors have the capacity to progressively disrupt both the activities of individual cells and the operating characteristics of networks of neurons throughout the life cycle, while antidepressant treatments act to reverse such injurious effects.
Conclusions We propose a central role for the regulation of synaptic connectivity in the pathophysiology of depressive disorder.
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INTRODUCTION |
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AN IDEAL NEUROBIOLOGY OF DEPRESSIVE DISORDER |
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Here, we attempt to draw together a range of recent neurobiological studies in order to construct a preliminary framework for an enriched neurobiology of depressive disorder.
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MOLECULAR AND CELLULAR FINDINGS: THE NEUROTROPHIC PERSPECTIVE |
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These are exciting observations for a number of reasons. First, BDNF belongs to a family of growth factors that control a variety of important neural activities ranging from cell differentiation during brain development to cell survival in the mature brain. Second, rats exposed to restraint stress show a reduction in BDNF expression in the hippocampus, and this effect is opposed by antidepressants (Smith et al, 1995). Third, direct infusion of BDNF itself into rat brain has putative antidepressant effects in preclinical animal models of depression (Siuciak et al, 1997). Last, but not least, these findings indicate a range of novel molecular targets for the development of new antidepressant therapies.
The fact that stress can down-regulate the expression of a protein responsible for the maintenance of cellular viability might relate to mechanisms that support adaptive stress responses, rather than harmful stress effects. However, the finding is consistent with the observation that a number of brain structures, including the hippocampus, may become atrophic in depressive disorder (e.g. Shah et al, 1998). It has been suggested that depression may represent a subtle neurodegenerative disorder, and that the antidepressant regulation of neuroprotective factors like BDNF acts to reverse such effects (Altar, 1999). Even electroconvulsive stimulation, so long viewed as potentially damaging to neurons, promotes BDNF expression and induces sprouting of hippocampal neurons (Vaidya et al, 1999).
These findings assume special significance now that it is apparent that new neurons are generated throughout life in the hippocampus of a variety of species, including humans. It has been suggested that a spectrum of factors threatens the balance of neural viability in the hippocampus, ranging from genetic influences, through the effects of stress and elevated corticosteroid levels, to sundry insults such as ischaemia, hypoglycaemia, neurotoxins and viral infections (Duman et al, 1997).
It is important to recognise that hippocampal cell viability may be sensitive to relatively subtle psychological events. Brief social stressors, for example, have been shown recently to interfere with cell proliferation in the dentate gyrus of the hippocampus of primates (Gould et al, 1998). In this study, adult marmosets that had been housed individually were transferred to the home cage of another, unfamiliar marmoset for 1 hour. This enforced intrusion on the territory of another monkey is very stressful, and though the intruder monkeys remained protected within the arena by a smaller cage, they adopted submissive postures and showed signs of distress and autonomic arousal. The intruder monkeys were then injected with a thymidine analogue, which is incorporated into proliferating cells, acting as a marker for neurogenesis. Immunohistochemical analysis showed subsequently that the stressor had reduced the rate of cell proliferation to less than two-thirds of the proliferation rate observed in the hippocampi of control monkeys. Antidepressant treatments may also prove protective in these circumstances: Madsen et al (2000) have recently shown that repeated electroconvulsive stimulation (ECS) in rats almost doubles the number of new-born cells observed in the dentate gyrus of the hippocampus compared with controls. Indeed, it is conceivable that this bolstering of neuronal survival may turn out to be a useful property of antidepressant treatments beyond depressive disorder. Potential applications include post-traumatic stress disorder, and more clearly neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
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PHYSIOLOGY: NETWORKS OF NEURONS |
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These technical and conceptual advances permit us to begin to ask questions about the dynamics of information processing in the brain such that neuropsychology and neurophysiology are drawn together in a way that traditional neurochemical analysis alone could never achieve. Recognising, for example, that stressors may change patterns of connection strength in neural networks begins to make tractable the analysis of the nature of the information processing (and its dysfunction) that might underlie the cognitive and emotional changes that accompany affective disorder. It is this potential which most sharply differentiates the perspective elaborated here from neuroreceptor accounts of the neurobiology of depressive disorder. Neural network models of psychopathology are already beginning to emerge (e.g. Jeffery & Reid, 1997).
The effects of antidepressant agents on BDNF and excitatory amino acid function described above may explain previous demonstrations of antidepressant-induced modulation of synaptic connectivity (e.g. Stewart & Reid, 1993). We have shown in several in vivo studies that repeated (but not single) ECS consistently enhances synaptic connectivity in the dentate gyrus of the rodent (Stewart & Reid, 1993; Reid & Stewart, 1997). These effects lasted for at least 40 days after the end of the course of ECS, and developed incrementally seizure by seizure during the course of stimulation. The maximum effect was reached only after four to six seizure applications, each spaced by 48 hours. These findings are consistent with clinical observations relating to the efficacy of electroconvulsive therapy (ECT) in humans. Prior administration of the NMDA-receptor-associated channel-blocker ketamine prevented the change in connectivity, implicating excitatory amino acid neurotransmission in the actions of ECS (reviewed by Petrie et al, 2000).
Given the important role that LTP may play in memory formation, the modification of plasticity observed might account for the amnesic effects of seizure activity (Reid & Stewart, 1997). However, we have recently reported that chronic administration of fluoxetine, which does not share the amnesic properties of ECS, induced similar up-regulation of connectivity in the dentate gyrus (Stewart & Reid, 2000). This does not exclude the interesting possibility that effects of ECS on synaptic plasticity in other subfields of the hippocampus, or in other brain structures, are responsible for the transient anterograde amnesia that follows seizure activity in humans and other species. This would imply that fluoxetine and ECT have differential effects on synaptic plasticity in different brain areas.
It seems likely that there are multiple routes to the changes in connectivity induced by different antidepressants. There is evidence that chemical antidepressants may interact directly with the excitatory amino acid systems that underpin changes in synaptic connection strength, in addition to enhancing BDNF expression. A number of different antidepressant agents have regulatory actions at the NMDA receptor complex and some NMDA receptor antagonists themselves have antidepressant properties in animal models that predict the clinical effectiveness of traditional drugs (Skolnick, 1999). These findings suggest that it is the ability to modify synaptic plasticity that is the crucial feature of clinically effective antidepressants, rather than the enhancement of neuronal survival alone (Petrie et al, 2000).
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STRESS AND SYNAPTIC PLASTICITY |
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Like humans, individual rats vary in their response to a given stressor. Indeed, variations in stress-induced excitatory synaptic changes correlate with variations in recognised somatic manifestations of stress, such as stomach ulcer formation. Henke (1990) has shown that stress is more likely to promote ulcer formation in the stomachs of rats that show a down-regulation of connectivity in the dentate gyrus of the hippocampus in response to restraint stress. Conversely, he observed that stress-resistant rats, which did not develop ulcers during the procedure, showed an increase in excitatory post-synaptic potential in the dentate cell fields. Furthermore, Henke was able to reduce ulcer formation in stressed rats by artificially inducing LTP via electrical stimulation of the afferent pathways to the dentate gyrus (Henke, 1989). This stress-protective change in electrophysiological signature produced by direct manipulation of hippocampal activity is consistent with the changes we have observed following chronic antidepressant administration and repeated electroconvulsive stimulation in rats (Stewart & Reid, 2000).
Studies that are more recent indicate that stressors may alter the dynamic balance between increases and decreases in synaptic connectivity such that LTD is favoured. Kim & Yoon (1998) have suggested that a complex relationship between past and current synaptic activity exists, which controls the plastic properties of neural networks (so-called metaplasticity a changing capacity for plasticity). They highlight the importance of intracellular calcium levels, regulated by excitatory amino acid receptors, in determining whether LTD (low calcium levels), LTP (high calcium levels) or excito-toxic vulnerability (very high calcium levels) occurs. Again, a continuum from cellular dysfunction to cell death is proposed, determined by the history of neural activity, which is in turn modulated by experience.
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ROLE OF GLUCOCORTICOIDS |
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Clearly, there is the potential for a dynamic interaction between stress, corticosterone, BDNF and synaptic plasticity modified by both the genetically determined integrity of the hippocampus, and its past history of psychological and physiological insults.
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EARLY ADVERSE EXPERIENCE AND HIPPOCAMPAL FUNCTION |
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Studies of the relationships between stressful experience and the plasticity of neural systems are contributing to an emerging biology of the impact of early experience and later adverse life events on limbic neural systems. A coherent account of the biology of early adversity and stressful life events (well-established risk factors in depressive disorder) will be crucial to any future satisfactory neurobiology of human affective disorder. The mechanisms of antidepressant action reviewed above clearly have the potential to interact with the pathoplastic effects of adverse experience described here.
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BRAIN MODULES: STRUCTURE AND NEUROPSYCHOLOGICAL FUNCTION IN DEPRESSION |
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HIPPOCAMPUS AND DEPRESSIVE DISORDER |
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Although there is little doubt that hippocampal damage has profound effects on cognitive function, it is unlikely that hippocampal dysfunction in depressive disorder is expressed purely as memory disorder. Rather than representing a passive casualty generating incidental memory failure, the dysfunctional hippocampus may also play an important role in the induction and maintenance of the depressed mood state itself. The hippocampus has a long and chequered career in the neurosciences, and a variety of functions have been ascribed to the structure over the years. Early researchers considered the hippocampus to have a primarily olfactory function, but later conceptualisations include the hippocampus in limbic circuits believed to be concerned with the apprehension and expression of emotion. It now seems likely that the hippocampus contributes to a range of activities: although much contemporary research focuses on its role in learning and memory, the stress-related changes in hippocampal function reviewed above have led to a reappraisal of its functions, not least its role in the regulation of corticosteroid function.
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SYNTHESIS |
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We have tried to follow a continuous thread from molecular events in the nuclei of individual cells, through the dynamic properties of neural networks and the brain structures that they subserve, to neuropsychological phenomena and the effects of social stressors. While we recognise that the experimental findings presented here are derived almost exclusively from animal studies, and that a great deal is yet to be discovered, we believe that a competent neurobiology of depressive disorder will eventually take this general form.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
---|
Altar, C. A. (1999) Neurotrophins and depression. Trends in Pharmacological Sciences, 20, 59-61.[CrossRef][Medline]
Bazin, N., Perruchet, P., De Bonis, M., et al (1994) The dissociation of explicit and implicit memory in depressed patients. Psychological Medicine, 24, 239-245.[Medline]
Drevets, W. C., Price, J. L., Simpson, J. R., et al (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 386, 824-827.[CrossRef][Medline]
Duman, R. S., Heninger, G. R. & Nestler, E. J. (1997) A molecular and cellular theory of depression. Archives of General Psychiatry, 54, 597-606.[Abstract]
Gould, E., Tanapat, P., McEwen, B., et al
(1998) Proliferation of granule cell precursors in the
dentate gyrus of adult monkeys is diminished by stress. Proceedings
of the National Academy of Sciences of the USA,
95,
3168-3171.
Henke, P. G. (1989) Synaptic efficacy in the entorhinaldentate pathway and stress ulcers in rats. Neuroscience Letters, 107, 110-113.[Medline]
Henke, P. G. (1990) Granule cell potentials in the dentate gyrus of the hippocampus: coping behaviour and stress ulcers in rats. Behavioural Brain Research, 36, 97-103.[Medline]
Jeffery, K. & Reid, I. C. (1997) Modifiable neuronal connections: an overview for psychiatrists. American Journal of Psychiatry, 154, 156-164.[Abstract]
Kehoe, P., Hoffman, J. H., Austin-LaFrance, R. J., et al (1995) Neonatal isolation enhances hippocampal dentate response to tetanization in freely moving juvenile male rats. Experimental Neurology, 136, 89-97.[CrossRef][Medline]
Kim, J. J. & Yoon, K. S. (1998) Stress: metaplastic effects in the hippocampus. Trends in Neurosciences, 21, 505-509.[CrossRef][Medline]
LeDoux, J. (1996) The Emotional Brain. New York: Simon and Schuster.
Levine, E. S., Crozier, R. A., Black, I. B., et al
(1998) Brain-derived neurotrophic factor modulates
hippocampal synaptic transmission by increasing N-methyl-D-aspartic
acid receptor activity. Proceedings of the National Academy of
Sciences of the USA, 95,
10235-10239.
Madsen, T. M., Treschow, A., Bengzon, J., et al (2000) Increased neurogenesis in a model of electroconvulsive therapy. Biological Psychiatry, 47, 1043-1049.[CrossRef][Medline]
Pavlides, C., Kimura, A., Magarinos, A. M., et al (1995) Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation. Neuroscience, 68, 387-394.[CrossRef][Medline]
Petrie, R. X., Reid, I. C. & Stewart, C. A. (2000) The NMDA receptor, synaptic plasticity and depressive disorder: a critical review. Pharmacology and Therapeutics, 87, 11-25.[CrossRef][Medline]
Reid, I. C. & Stewart, C. A. (1997) Seizures, memory and synaptic plasticity. Seizure, 6, 351-359.[Medline]
Schaaf, M. J., de Jong, J., de Kloet, R., et al (1998) Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone. Brain Research, 813, 112-120.[CrossRef][Medline]
Shah, P. J., Ebmeier, K. P., Glabus, M. F., et al (1998) Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. British Journal of Psychiatry, 172, 527-532.[Abstract]
Siuciak, J. A., Lewis, D. R., Wiegand, S. J., et al (1997) Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacology, Biochemistry and Behavior, 56, 131-137.[CrossRef][Medline]
Skolnick, P. (1999) Antidepressants for the new millennium. European Journal of Pharmacology, 375, 31-40.[CrossRef][Medline]
Smith, M. A., Makino, S., Kvetnansky, R., et al (1995) Stress alters the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. Journal of Neuroscience, 15, 1768-1777.[Abstract]
Stewart, C. & Reid, I. (1993) Electroconvulsive stimulation and synaptic plasticity. Brain Research, 620, 139-141.[Medline]
Stewart, C. & Reid, I. (2000) Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology, 48, 217-223.
Vaidya, V. A., Siuciak, J. A., Du, F., et al (1999) Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience, 89, 157-166.[CrossRef][Medline]
Vickery, R., Morris, S. H. & Bindman, L. J.
(1997) Metabotropic glutamate receptors are involved in
long-term potentiation in isolated slices of rat medial frontal cortex.
Journal of Neurophysiology,
78,
3039-3046.
Xu, L., Holscher, C., Anwyl, R., et al
(1998) Glucocorticoid receptor and protein/RNA synthesis
dependent mechanisms underlie the control of synaptic plasticity by stress.
Proceedings of the National Academy of Sciences of the
USA, 95,
3204-3208.
Received for publication June 29, 1999. Revision received July 30, 2000. Accepted for publication August 14, 2000.