Long-term potentiation and changes seen in depression

S. H. Zaman

Mental Health Unit, Gloucester House, Southmead Hospital, Bristol BS10 5NB, UK

R. Zaman

Bedfordshire and Luton Community NHS Trust, Mental Health Service, Bedford, UK

Reid & Stewart (2001) review evidence for a neurobiological basis of depression and it is suggested that brain plasticity plays a major role. These plasticity changes involve neuronal atrophy, neurogenesis, dendrite involution and formation, and long-term potentiation (LTP). Electroconvulsive therapy (ECT) and antidepressants enhance LTP and, as Reid & Stewart imply, the benefits (and adverse effects) of such treatments may be due to an enhancement or saturation of LTP. We question whether abnormal LTP per se is a critical neurobiological path to the changes seen in depression. We support the view that alterations in structural plasticity, as opposed to LTP, are more critical. Antidepressants, ECT, depression and stress can all modulate neuronal structure and LTP has been shown to be abnormal in models of depression and stress, but it does not follow that abnormal LTP is a prerequisite for these states, even though LTP is accepted to be important in, for example, associative learning.

In studies where LTP has been shown to alter neuronal structure, the increase in synaptic efficacy (assayed electrophysiologically) occurs within seconds to minutes but the earliest detected structural changes take at least 20 minutes (Yuste & Bonhoeffer, 2001). This time frame also does not correlate with the time required for the effects of antidepressant treatment (including ECT) - structural changes correlate better. Furthermore, although LTP is associated with morphological changes, these do not necessarily contribute to the potentiation (Yuste & Bonhoeffer, 2001). This casts doubt on the notion that the alterations in LTP are critical to the pathophysiological mechanism. We support the notion that the primary pathology is due to maladaptive neuronal structural change (Vaidya & Duman, 2001). The most likely reason why LTP can be affected by stress and depression, or by treatments for depression, is because such stimuli activate neuronal molecular signalling pathways. These pathways overlap with each other and with the signalling pathways that lead to dendritic structural changes.

EDITED BY MATTHEW HOTOPF

REFERENCES

Reid, I. C. & Stewart, C. A. (2001) How antidepressants work. New perspectives on the pathophysiology of depressive disorder. British Journal of Psychiatry, 178, 299-303.[Abstract/Free Full Text]

Vaidya, V. A. & Duman, R. S. (2001) Depression: emerging insights from neurobiology. British Medical Bulletin, 57, 61-79.[Abstract/Free Full Text]

Yuste, R. & Bonhoeffer, T. (2001) Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annual Review of Neuroscience, 24, 1071-1089.[CrossRef][Medline]


 

Authors' reply

I. Reid and C. Stewart

Department of Psychiatry, University of Dundee, Ninewells Hospital, Dundee DDI 9SY, UK

EDITED BY MATTHEW HOTOPF

It was kind of Drs S. H. & R. Zaman to take an interest in our paper. In their thoughtful response they draw attention to the time course of LTP induction (seconds to minutes), and point out that this does not correlate with the time required for the effects (presumably, clinical response) of antidepressant treatments. The key issue is not the speed with which LTP induction itself occurs, which is unchanged by stress or antidepressant treatments (Stewart & Reid, 1993). It is rather the time course of changes induced in the regulation of LTP by antidepressant treatments (the so-called ‘metaplasticity’ referred to in our paper) that is important. This develops gradually, requiring at least six spaced ECT treatments for maximum effect (Stewart et al, 1994) or 14 days of fluoxetine treatment (Stewart & Reid, 2000). Interestingly, the effects of ECT on the degree to which LTP can be induced are detectable even 40 days after the end of a course (Stewart & Reid, 2000). These periods each correlate very nicely with antidepressant response, with the last described also mirroring the time course of relapse after successful ECT treatment in humans without antidepressant prophylaxis. Changes in excitatory post-synaptic potentials are seen, however, immediately after a single electroconvulsive application in experimental studies (Stewart et al, 1994), but they are smaller and more transient than those seen after a series of applications. This also accords with clinical observation: severely ill patients receiving ECT often show clear but transient responses after the first treatment in a course.

Of course, these are electrophysiological observations, and they may be mediated by ultrastructural neuronal changes. In this sense, we agree with the subtle point being made by Zaman & Zaman. Our aims are to draw together rather than disaggregate structural and functional phenomena. That is why we used the term connectivity in the review to refer to both functional and ultrastructural (e.g. dendritic) changes underlying the plasticity of neuronal connections, which we wished to distinguish from more gross effects such as cell death or proliferation. The fact that "molecular signalling pathways" to "dendritic structural changes" and to LTP overlap is precisely why we classed them together as candidate contributors to the neurobiology of depressive disorder. They may be dissociable, as Zaman & Zaman point out, but this is not in itself evidence for or against the role of the regulation of LTP in affective disorder.

In any event the functional (electrophysiological plasticity) and structural changes (microanatomical plasticity) described in our review are each associated in reciprocal fashion with stress and antidepressant treatments, respectively - neither structural nor functional changes have been shown to have a causal role in depressive disorder. It does not allow that either phenomenon is a prerequisite for depressive states.

REFERENCES

Stewart, C. & Reid, I. (1993) Electroconvulsive stimulation and synaptic plasticity in the rat. Brain Research, 620, 139-141.[Medline]

Stewart, C. & Reid, I. (2000) Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology, 148, 217-223.[CrossRef][Medline]

Stewart, C. Jeffrey, K. & Reid, I. C. (1994) LTP-like synaptic efficacy changes following electroconvulsive stimulation. Neuroreport, 5, 1041-1044.[Medline]





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