Title - Feature Finding
Featured Finding Figure
Identifying the molecular alterations that underlie the pathophysiology of critical clinical features of schizophrenia is an essential step in the rational development of new therapeutic interventions for this devastating illness. Cognitive deficits, such as the impairments in working memory that arise from dysfunction of the dorsolateral prefrontal cortex (DLPFC), are a major determinant of functional outcome in schizophrenia. The reported involvement of disturbances in glutamate, dopamine (DA) and GABA neurotransmission in the pathophysiology of working memory impairments in schizophrenia raises the possibility of a cascade of molecular events that could link these disturbances, and thereby suggesting that the molecular alterations most proximal to the pathophysiology of prefrontal dysfunction offer the most promise as targets for new drug development. In this figure we provide a hypothetical model for such a cascade. Hypofunction of NMDA receptors mediating excitatory inputs to prefrontal pyramidal cells in schizophrenia leads to decreased activity in cortical excitatory projections to mesencephalic DA cell nuclei resulting in decreased activity of DA neurons projecting to the DLPFC and increased activity of DA cells projecting to the striatum. Reduced DA levels in DLPFC lead to compensatory, but functionally insufficient, upregulation of D1 receptors. NMDA hypofunction and altered D1 mediated signaling may reduce the activity of parvalbumin (PV)-positive chandelier neurons, producing a decrease in activity-dependent expression of the mRNA for GAD67, a synthesizing enzyme for GABA. Reduced GAD67 presumably leads to decreased GABA release, and thus to downregulation of the GABA transporter (GAT1) in chandelier cell cartridges and upregulation of postsynaptic α2 GABAA receptors in the axon initial segment of DLPFC pyramidal cells. This alteration in chandelier cell inputs to pyramidal neurons is thought to contribute to the impairments in the synchronization of pyramidal neurons at gamma band frequencies required for working memory.
Morris H, Hashimoto T, Lewis DA: Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia. Cerebral Cortex 18: 1575-1587, 2008.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
Pittsburgh, Pennsylvania 15213-2593
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