Exploration of KCC2: Role in Schizophrenia

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DESCRIPTION (provided by applicant): This is an exploratory/development grant (R21) proposal in response to NIMH RFA#PA-00-073. The K-CI Co-Transporter (KCC2) is neuronal specific and widely distributed in the central nervous system. KCC2 serves a dual function in neurons: the maintenance of low intracellular chloride ([CI]i) and the buffering of external potassium ([K]o) concentrations in the brain. Functionally, KCC2 is coupled with GABAA receptors whose activation allows anions (predominantly CI-) to flow into neurons, producing GABA's principal synaptic function - inhibition. Whether GABAA receptor activation leads to inhibition or excitation depends upon the value of its reversal potential (EGABAA). The reversal potential value is primarily determined by an electrochemical gradient of the CI across the membrane; KCC2 plays a pivotal role in regulating neuronal [Cl]i homeostasis. Thus, KCC2 regulates the physiological functions of GABAA receptors, namely, synaptic inhibition in normal adult CNS neurons, while also synaptic excitation in normal developing or neonatal neurons, and possibly - in a maladaptive manner - in disease affected neurons. The GABAergic system, the main inhibitory system in the brain, is reported to malfunction in schizophrenia (SCZ). SCZ is a complex mental disorder characterized by a debilitating disturbance of cognitive function and behavior that may result from a dysfunction of multiple CNS neurotransmission systems including the GABAergic system. However, the expression and function of the KCC2 transporter have not been studied in schizophrenic brains or in animal models of schizophrenia. We propose to explore the role of KCC2 in a chronic phencyclidine (c-PCP) rat model of schizophrenia. The experiments will test the hypothesis that in rats treated chronically with PCP, KCC2 is functionally down-regulated and/or its expression is altered in neurons of the medial prefrontal cortex (mPFC). The mPFC has long been implicated in the pathogenesis of schizophrenia. The specific aims are threefold: namely, 1) compare the synaptic physiology of GABAA receptors in the prefrontal cortex of normal and c-PCP rats; 2) determine the value of GABAA receptor reversal potentials (EGABAA), for GABAA receptors at synaptic and non-synaptic sites in normal and c-PCP rats, respectively; and, 3) determine the levels of protein expression of KCC2 while investigating its pharmacological manipulation with an antagonist, furosemide, in normal and c-PCP rats. Results from the proposed study may provide an impetus to consider a novel pathogenesis for schizophrenia, while at the same time providing a basis for a more effective pharmacotherapy.