Deficits in cognitive functions subserved by the dorsolateral prefrontal cortex (DLPFC) are among the most devastating consequences of schizophrenia. Alterations in the intrinsic circuitry of the DLPFC, including inhibitory interneurons, appear to contribute to the observed deficits. Recent post-mortem studies have demonstrated a consistent reduction in GABAergic markers in subjects with schizophrenia, which may be most prominent in the parvalbumin-containing subset of interneurons (PV interneurons). However, how alterations in these inhibitory neurons may be related to the cognitive deficits present in schizophrenia requires an understanding of the normal, fundamental mechanisms that govern the operation of inhibitory circuits in the primate DLPFC. In order to address this question, this proposal begins with an anatomophysiological identification of inhibitory neurons, and follows with studies designed to test the hypothesis that PV interneurons, provide tight temporal coupling of pyramidal cells' outputs to their inputs, suggesting their critical role in retaining information selectivity (given that it is coded in spike timing) during cortical information processing. Thus, alterations in these GABA neurons are proposed to have detrimental effects on the temporal fidelity and selectivity of pyramidal cells outputs, resulting in loss of their specific tuning in DLPFC. We suggest that this mechanism contributes to the pathophysiological basis for the cognitive deficits in thought processing and working memory observed in schizophrenia. The power of the proposed studies to test these hypotheses derives from several factors. First, the studies are conducted in young adult macaque monkeys, whose highly developed DLPFC makes this species unexcelled for research into the structure-function relationships underlying human mental illnesses. Second, the approach utilizes a living slice preparation, the ideal means to study functional intrinsic circuitry at the cellular and synaptic levels of resolution required to rigorously test our hypotheses. Third, the studies will be conducted using a newly developed experimental set-up that allows simultaneous patch clamp electrophysiological recordings from up to 8 neurons, providing a high yield of connected cell pairs, triplets and quadruplets. Finally, all physiological observations will also be combined with morphological reconstructions of identified neuronal circuits, allowing correlations between structure and function.
