This project will focus on the role of chemokines in modulating neuronal cell intracellular calcium signaling and excitability as a model for neurological dysfunction in HIV-1 infection. The hypothesis is that HIV-1 infection in the CNS induces release of soluble chemokines (IP-10, RANTES, MIP-1 alpha, IL-8) which bind neuronal chemokine receptors and activate signal transduction pathways that subserve normal neuronal cell responses to neuroeffector molecules. This may involve both short-term and long-term activation of MAP kinase. The result may be impairment of normal physiological responses in neurons, resulting in pathological dysfunction. The investigator will utilize rodent primary mixed hippocampal cultures from wild-type as well as selected transgenic animals provided to address four specific aims: 1) to determine the sensitivity and response of cultured rodent hippocampal neurons to acutely applied chemokines; 2) to identify the signaling pathways involved in neuronal chemokine receptor activation; 3) to determine whether acute chemokine exposure alters neuronal responsiveness to glutamate; and 4) to determine the effects of chronic chemokine exposure on neuronal and astrocytic electrophysiological responses. The overall design will address effects of both acute and chronic chemokine exposure on neuronal cell function and will include examination of two distinct classes of neurons, excitatory glutamatergic and inhibitory GABAergic neurons.
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