David B. Carr - US grants

DESCRIPTION: The prefrontal cortex (PFC) plays important roles in cognitive and affective function. Dysfunction within PFC circuitry is strongly implicated in the pathophysiology of schizophrenia, particularly in the expression of negative symptoms. The ability of atypical antipsychotics such as clozapine to ameliorate these negative symptoms has focused attention on the serotonin (5-HT) as well as dopamine (DA) modulatory systems within the PFC, as these drugs are potent antagonists at both 5-HT and DA receptors. Despite the importance of these two neuromodulatory systems in regulating PFC neuronal activity, very little is known as to how they affect the ionic conductances that shape information processing within PFC cells. Moreover, almost nothing is known as to how 5-HT and DA interact at the level of individual PFC neurons. To address these issues, a research and training plan is proposed utilizing a combination of electrophysiological, pharmacological and molecular biological techniques to achieve two specific aims. The first is to examine the effect of 5-HT2a/c receptor stimulation on Na+ currents in acutely isolated PFC neurons and to characterize the mediating signaling cascade. The second aim is to characterize the nature and mechanism of interaction of 5-HT2a/c and DA1/5 signaling pathways on Na+ currents will be examined. The achievement of these aims will provide vital information necessary to construct accurate, integrative models of PFC function as well as dysfunctional states such as schizophrenia.

[unreadable] DESCRIPTION (provided by applicant): The orbital prefrontal cortex (oPFC) plays important roles in the processing of reward related information and the use of that information to guide decision making. Studies in humans and primates have shown that PFC serotonin (5HT) depletion produces deficits in cognitive tasks that are sensitive to the integrity of the oPFC. Furthermore, converging lines of evidence suggest dysfunction of the oPFC and its 5HT input as contributing factors in the pathophysiology of several neuropsychiatric disorders, including schizophrenia, depression, and obsessive-compulsive disorder. Taken together, these observations suggest that an intact 5HT innervation is vital to the proper functioning of the oPFC. Unfortunately, the mechanisms through which 5HT influences oPFC neuronal activity are still poorly understood. The available anatomical and electrophysiological evidence indicates that GABA local circuit neurons are an important target of 5HT signaling. GABA neurons are a heterogeneous population of cells that differ in their electrophysiological properties, axonal targets and expression of calcium binding proteins and neuropeptides. Because of these distinctions, it is thought that these different populations mediate very distinct roles in regulating the activity of cortical networks. The central hypothesis of this proposal is that these different neurochemically identified populations of GABA local circuit neurons within the oPFC express distinct complements of 5HT receptor subtypes and that this specificity in receptor expression is reflected in how these populations of GABA cells respond to 5HT. To test this hypothesis, we propose to use a combination of electrophysiological and molecular methods to address two specific aims. Specific Aim 1 will use single cell RT-PCR profiling of acutely dissociated GAD67-GFP labeled neurons to determine the coordinated expression of 5HT receptor subtypes within neurochemically identified populations of oPFC local circuit neurons. Specific Aim 2 will utilize whole cell in vitro patch clamp of GFP labeled GABA local circuit neurons, coupled with subsequent neurochemical identification using single cell RT-PCR, to determine how different neurochemically identified populations of GABA local circuit neurons respond to 5HT receptor stimulation. Elucidating the expression of 5HT receptor subtypes within identified populations of oPFC local circuit neurons, combined with a better understanding of how 5HT influences the activity of these cells, is vital in constructing accurate models of information processing within the oPFC. Moreover, these studies may also provide important insights into new therapeutic targets for treating neuropsychiatric disorders such as schizophrenia, OCD and depressive disorders. PUBLIC HEALTH RELEVANCE: Dysfunction within the orbital cortex has been observed in schizophrenia, depression, and obsessive- compulsive disorder. The studies described in this application may provide vital new insights into both the etiology of these disorders as well as potential new therapeutic targets for their treatment. [unreadable] [unreadable] [unreadable]