Chemical transmission in the central nervous system (CNS) relies on effective communication between neurons. This process is dependent upon the spatially correct formation of presynaptic terminals and the localization of postsynaptic receptors. The development and assembly of glutamatergic synapses is of particular importance because the majority of excitatory transmission in the CNS occurs via ionotropic glutamate receptors. As such, impaired function or expression of glutamate receptors (GluRs) is implicated in several neuropathologies including certain forms of epilepsy, stroke/ischemia, head trauma, cognitive impairments, and neurodegenerative disease. Therefore, the targeting and trafficking of GluRs is of considerable interest but remains poorly understood. A recent forward genetic screen for mutations that affect GluR cluster formation at the Drosophila neuromuscular junction revealed that the autophagy-specific gene 1 (Atg1) is necessary for the formation of glutamate receptor (GluR) clusters. Atg1 is required for autophagy, a well-conserved process that removes cytoplasm and organelles from cells. Animals lacking a functional atg1 gene exhibit a significant reduction in GluR cluster size. This mutation specifically affects GluRs as there is no observed difference in other synaptic proteins examined. We will investigate whether mutations in atg1 alter the transcription or translation of GluRs and determine whether atg1 affects GluR cluster formation by signaling through known pathways that regulate cell growth. Determining the role of atg1 in GluR cluster formation by analyses of atg1 mutants will improve our understanding of both autophagy both autophagy and the mechanisms that govern GluR expression and localization.
The majority of communication between the cells of the brain utilizes the neurotransmitter glutamate. Glutamate receptors cluster in cells adjacent to areas where glutamate is released. Impaired function or expression of glutamate receptors is implicated in several neuropathologies including certain forms of epilepsy, stroke/ischemia, head trauma, cognitive impairments, and neurodegenerative disease. Therefore, the expression and localization of glutamate receptors is of considerable interest but remains poorly understood. Using genetic techniques, we determined mutations of the autophagy-specific gene 1 (Atg1) cause a significant reduction in number of glutamate receptors in cells. For this project, we will investigate the mechanism(s) by which Atg1 affects glutamate receptors. Determining the role of atg1 in glutamate receptor cluster formation by analyses of atg1 mutants will improve our understanding of both autophagy and the mechanisms that govern glutamate receptor expression and location.
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