Neuroleptics that antagonize G-protein coupled, dopaminergic and serotonergic receptors to alleviate the symptoms of schizophrenia. Prolonged treatment with neuroleptics 'remodels'circuits of the prefrontal cortex (PFC) and striatum, ameliorating the symptoms of the disease. It is our central hypothesis is that the induction of remodeling depends upon the ability of neuroleptics to antagonize G-protein coupled, D2, D1, and 5-HT2 receptors, triggering cell-type specific adaptations in striatal and cortical neurons. Neuronal dendrites are likely to be critical targets oi this remodeling, being directly implicated in the schizophrenic neuropathology. D2, D1 and 5-HT.. receptors richly invest dendritic regions of key PFC and striatal neurons and have been implicated in modulating dendritic electrogenesis, synaptic integration and plasticity. Dysregulation of dendritic function by D2, D1 and 5-HTj receptors provides a potential explanation for the apparent involvement of glutamatergic signaling in schi/ophrcnia. Yet, very little is known about how neuroleptics and neuroleptic-sensitive receptors influence dendritic electrogenesis, synaptic integration and plasticity in functionally relevant subpopulations of PFC and striatal neurons. The central goal of the project is to help fill this gap in our understanding. There are two major obstacles blocking achievement of this goal. One obstacle is that the neurons within both the PFC and striatum are heterogeneous in their expression of neuroleptic-sensitive GPCRs. The recent development of BAC transgenic mouse lines in which neurons expressing D2 and D1 receptors are fluoresccntly tagged has effectively removes this obstacle. Another major obstacle is the inaccessibility of dendritic regions to physiological study. The recent development of two photon laser scanning microscopy (2PLSM), when used in conjunction with patch clamp techniques, diminishes this obstacle, opening these critical dendritic regions to investigation. This proposal takes full advantage of these new developments to complement our skills in single cell molecular profiling, electrophysiological analysis of ion channel modulation and computational neuroscience to pursue three specific aims:
Specific aim 1 is to characterize, in identified PFC and striatal neurons, short- and long-term neuroleptic-induced adaptations in i:he expression and modulation of voltage dependent ion channels thought to control dendritic electrogenesis.
Specific Aim 2 is to characterize short- and long-term neuroleptic-induced adaptations in D2, D1, and 5-HT2 receptor modulation of dendritic electrogenesis and glutamatergic synaptic integration in identified PFC'and striatal neurons.
Specific Aim 3 is to characterize in identified PFC and striatal neurons short- and long-term neuroleptic-induced adaptations in dopaminergic modulation of glutamatergic synaptic plasticity. For each of these aims, pursuit of the adaptations will be tightly linked to the other studies proposed in this Conte Center, providing a physiological complement to the molecular, biochemical and behavioral approaches they employ.
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