Leonid Krimer - US grants

DESCRIPTION: (Adapted from the Investigator's Abstract) The prefrontal region and its function, working memory, are both impaired in schizophrenia. In order to fulfill the PI's long-term career goal of uncovering a biological basis of schizophrenia, the PI proposes to study local circuitry in primate prefrontal cortex and the neuronal signaling mechanisms underlying working memory in normal and pathological conditions. This career path promises to translate the understanding of functional circuit analysis into clinically relevant hypotheses of neuropathology in schizophrenia. The immediate project proposed here asks about local excitatory neuronal signaling and its modulation by dopamine in prefrontal cortex in normal nonhuman primates and in an amphetamine-treated monkey model of schizophrenia. Pyramidal-to-pyramidal and pyramidal-to-nonpyramidal connections will be studied in a novel in vitro living slice preparation using dual somatic recording via the whole cell patch clamp technique. Electrophysiological, pharmacological and anatomical analyses of these connections will be performed. The neuromodulatory effect of dopamine on identified excitatory and inhibitory synaptic transmission will be explored. Experiments will be conducted initially in ferrets and then in nonhuman primates and in human temporal cortex surgically removed for the treatment of intractable epilepsy. This project will allow a detailed examination of a realistic experimental unit of normal prefrontal cortical excitation in primates and a characterization of alterations in experimental nonhuman primate models of schizophrenia. The project will advance our understanding of the circuit basis of information processing mechanisms in the primate prefrontal cortex. The proposed multidisciplinary approach requires fundamental knowledge of electrophysiology, pharmacology, ion channels, statistics and electron microscopy, and the candidate's previous training is limited mostly to neuroanatomy. If this grant is awarded, the candidate will receive formal neuroscience coursework equivalent to a Ph.D. degree in neuroscience and conduct the proposed research projects in the rich scientific environment of the Center for Neuroscience of Mental Disorders.

DESCRIPTION (provided by applicant): 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.