Schizophrenia Research Forum - A Catalyst for Creative Thinking

Forum Discussion: Functional and Dysfunctional Synaptic Plasticity in Prefrontal Cortex


In our Forum Discussion "journal club" series, the editors of some of the journals in the field provide open access to the full text of a recent article. In this case, we thank the Society for Biological Psychiatry, not to mention Elsevier Journals, for providing access for six months to an article in Biological Psychiatry. A short introduction by a journal editor gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on....

Goto Y, Yang CR, Otani S. Functional and dysfunctional synaptic plasticity in prefrontal cortex: roles in psychiatric disorders. Biol Psychiatry. 2010 Feb 1; 67(3):199-207. Abstract

View the full text of the article.

View Comments By:
Brian Morris — Posted 25 March 2010


Background Text
By Paul Harrison, University of Oxford

Synaptic plasticity has become embedded in, and is increasingly central to, contemporary explanatory models of brain function. It is equally prominent in models of the pathophysiological basis of most psychiatric disorders including schizophrenia, addiction, mood disorder, and Alzheimer’s disease. Goto, Yang, and Otani provide a valuable, elegant, and concise review (complemented by extensive supplementary online material for aficionados) of synaptic plasticity in the prefrontal cortex (PFC). It is a perfect starting point for those wanting to get into this fast-moving and fascinating field.

Goto and colleagues note the relative neglect of the PFC compared to the hippocampus with regard to synaptic plasticity. They summarize diverse evidence which shows—strikingly, though perhaps not surprisingly—that the PFC indeed possesses the capability and machinery for various forms of synaptic plasticity, albeit using molecules and mechanisms that likely differ, at least in part, from those in the hippocampus. Another focus of the review is the key role that dopamine plays in the modulation of PFC synaptic plasticity, including the balance of D1 versus D2 receptor activation, and the direct and indirect interactions of dopamine with other transmitter systems, notably glutamate (via N-methyl-D-aspartate receptors and group II metabotropic receptors). Finally, Goto and colleagues briefly introduce the ways in which dopamine-mediated PFC synaptic plasticity may go awry in psychiatric disorders, and its candidacy as a cellular mechanism for therapeutic remediation.

Any topic as complex, multifaceted, and in places controversial, as this one raises many areas for discussion. Readers will have their favorite (suggestions, please!), but to get a debate going, how about the following?

1. What are the known similarities and differences between the mechanisms of PFC synaptic plasticity and those in the hippocampus? Similarly, what is the extent of intra-PFC heterogeneity (e.g., ventral versus dorsal)?

2. How readily should we extrapolate from mechanisms (and terminologies) studied in experimental animal models to humans? For example, to what extent is “long-term- potentiation-like facilitation” (elicited in humans using paired-associate stimulation or transcranial direct current stimulation) the same as classical long-term potentiation (defined based on electrophysiological recordings)? Can we know? Does it matter at this stage?

3. As the authors note, several neuromodulators other than dopamine are also involved in PFC synaptic plasticity. Do we yet know the relative roles of, and interactions between, these various modulators? Can a molecular dissection be made in terms of their contributions to different components or mechanisms of plasticity, or to different neural circuits, synaptic populations, or developmental stages? Or to any other categorization or dimension of plasticity?

4. How can current notions and theories of PFC synaptic plasticity be made more specific? Are there refutable hypotheses about its nature, location, or functional significance that can help take us forward?

Comments on Online Discussion
Comment by:  Brian Morris
Submitted 25 March 2010
Posted 25 March 2010

This is an important and developing area, and this review gives an excellent summary of our current knowledge. It is indeed remarkable how much of our understanding of the neurochemical, genetic, and environmental basis of schizophrenia is consistent with dysfunctional plasticity in the prefrontal cortex and anatomically linked brain regions.

Many of the best-characterized forms of plasticity are dependent on activation of the N-methyl-D-aspartate (NMDA) class of glutamate receptor (Morris, 2004). NMDA receptor antagonists have the ability to exacerbate symptoms in patients with schizophrenia, induce schizophrenia-like changes in control subjects, and mirror many of the neurobiological and behavioral characteristics of schizophrenia in animal models. Hence, one possibility is that schizophrenia reflects impairment in NMDA receptor-dependent plasticity. However, a consequence of NMDA receptor antagonist administration is a paradoxical and rather dramatic elevation of glutamate release in the prefrontal cortex and connected areas, although the NMDA receptors presumably remain blocked (Morris et al., 2005). As noted by the authors, this suggests the alternative possibility that glutamatergic (but NMDA receptor-independent) plasticity mechanisms are of particular importance for schizophrenia.

I would argue that an understanding of the neural circuits involved will be key to advancing our understanding of how and why plasticity may be perturbed in schizophrenia. The prefrontal cortex is strongly linked—both anatomically and functionally—to such regions as the nucleus accumbens, mediodorsal thalamus, and hippocampal formation (O'Donnell and Grace, 1998), and we know that hippocampal plasticity has a profound impact on prefrontal cortex function (Canals et al., 2009). Is the main locus of plasticity dysfunction in schizophrenia at intrinsic cortical connections, in hippocampo-cortical or thalamo-cortical pathways, or in prefrontal efferent pathways (or maybe all of these)?

References:

Canals S, Beyerlein M, Merkle H, Logothetis NK. Functional MRI evidence for LTP-induced neural network reorganization. Curr Biol. 2009;19:398-403. Abstract

Morris BJ. Neuronal plasticity. In Davies RW, Morris BJ (Eds.), Molecular Biology of the Neuron, 2nd ed. Oxford, UK: Oxford University Press. 2004;pp 357-86.

Morris BJ, Cochran SM, Pratt JA. PCP: from pharmacology to modelling schizophrenia. Curr Opin Pharmacol. 2005;5:1-6. Abstract

O'Donnell P, Grace AA. Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull. 1998;24:267-83. Abstract

View all comments by Brian Morris