Muscarinic acetyicholine receptors (mAChR) play a key role in the central nervous system, where they are involved in such functions as memory, learning, control of movement, and the regulation of circadian rhythms. The long-term goal of this research is to elucidate the mechanisms which regulate the expression and function of mAChR in the nervous system. Work from a number of laboratories has suggested that different subtypes of mAChR are differentially localized in cells, and this laboratory has demonstrated that different subtypes of mAChR are differentially localized in polarized cells and begun to identify sorting signals responsible for this differential localization. This proposal will determine the molecular basis and mechanisms responsible for generation of this asymmetry, and determine the relevance of these sorting pathways to the localization and function of the mAChR in the nervous system in vivo. Different mAChR subtypes have been implicated in different functions in the central nervous system, but it is difficult to unambiguously assign functions to specific receptor subtypes in vivo. This laboratory has created knockout mice lacking the M1 receptor and demonstrated that the M1 receptor plays a crucial role in the activation of phospholipase C and mitogen-activated protein kinase pathways in the forebrain and in generation of seizures in the pilocarpine model of epilepsy. This proposal will use these mice to determine the role the M1 receptor in the regulation of processing of the Alzheimer's precursor protein, to determine the pathways specifically involved in pilocarpine-induced seizures, and to determine the role of the M1 receptor in both signaling pathways and behavioral responses of the striatum. The identification of the factors responsible for the regulation of expression, localization, and function of the macromolecules involved in synaptic transmission is a problem of fundamental importance in cell and neurobiology. In addition, this research is of clinical importance because of the role of the mAChR in learning, memory, the cognitive defects in Alzheimer's disease, and the movement disorders in Parkinson' s disease. The elucidation of the factors involved in the regulation and function of mAChR may aid in understanding the etiology and possible treatment of a variety of neurological and mental abnormalities.
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