Glutamate is the primary excitatory neurotransmitter utilized by neurons in the central nervous system. Despite the prominence of glutamate as a vehicle for normal CNS function, it is also a potent neurotoxin when synaptic levels remain elevated above normal resting concentrations (approximately 1 muM) even for a short interval. Neural toxicity can occur due to release of transmitter glutamate that exceeds the capacity of the usual mechanisms for clearance of glutamate from the synapse, and/or when function of the clearance mechanisms themselves become compromised. Our preliminary work shows that localized biochemical signals modify glutamate reuptake by rat brain astrocytes in ways that can either compromise or enhance the clearance process. Astrocytes are known to play a prominent role in the clearance of synaptic glutamate. This proposal focuses on the role that astrocyte glutamate transport systems play in maintaining extracellular glutamate concentrations at levels which allow appropriate ongoing function of neural transmission events. Primary aims are to define the biochemical regulatory mechanisms which modulate active and passive astrocytic glutamate transport systems that determine steady state intra- and extra-cellular CNS glutamate levels. The renewal builds on recent preliminary work in which we have shown that astrocytic glutamate clearance from the synapse by the GLAST cotransport protein can be markedly stimulated by various 'signal molecules' which implicate the importance of cellular events involving protein kinase C, protein tyrosine kinase, phosphoprotein phosphatases, and 'targeting' of transport protein to the plasma membrane.
Specific aims are described which focus on providing detail for the role each of these processes plays in regulating astrocytic glutamate transporter activity and therefore of tempering the excitotoxic 'risk' that elevated synaptic glutamate levels otherwise represent. Our observations carry substantial health ramifications because they raise the interesting likelihood that synaptic clearance of glutamate is up-regulated or down-regulated in response to molecular signals acting in or on the astrocyte. This proposal aims at providing mechanistic definition for those regulatory mechanisms.
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