Plasticity of glutamatergic synapses is important in the storage of information in the brain. Neuronal and glial plasma membrane glutamate transporters play major roles in removing released glutamate from the synaptic cleft. Although the function of glutamate transporters has received considerable attention, only recently has it been demonstrated that glutamate uptake is regulated during expression of long-term synaptic plasticity. Glutamate uptake is increased during long-term sensitization in Aplysia, during LTP in the hippocampus of the rat, and during morphine addiction and withdrawal in the rat. These findings suggest that long-term regulation of glutamate uptake during changes in synaptic efficacy may be a phylogenetically conserved mechanism that occurs along with different types of synaptic plasticities. Furthermore, deficiencies in glutamate uptake have been implicated in a number of diseases including ALS, epilepsy, and Alzheimer's. Our long-term goal is to elucidate the general principles and functions of regulation of synaptic glutamate uptake associated with synaptic plasticity.
Our specific aims address the induction, expression, maintenance, and function of long-term changes in glutamate uptake that occur as a result of sensitization training in Aplysia. The proposed research has 4 specific aims:
Aim 1 is to characterize the activity of Aplysia glutamate transporters expressed in sensory neurons and Xenopus oocytes. In this aim, we will study the properties of an Aplysia glutamate transporter (ApGT1) expressed in oocytes following injection of ApGT1 cDNA.
Aim 2 is to determine the induction mechanisms that produce the long-term increase in glutamate uptake. We will study the roles of TGF-beta and C/EBP in mediating the long-term effects of sensitization training.
Aim 3 is to determine the mechanisms of expression/maintenance that are responsible for the increase in glutamate uptake. We will study whether sensitization training alters levels of ApGT1 mRNA, levels of ApGT1 protein, and synthesis of ApGT1 protein. We will also investigate the half-life of ApGT1 protein.
Aim 4 is to determine the physiological role of regulation of glutamate uptake. We will study modulation of regulation of glutamate uptake and test the hypothesis that the function of the increase in glutamate uptake is to reduce postsynaptic receptor desensitization. In addition to elucidating mechanisms of induction, expression, and maintenance, our results will elucidate physiological roles of regulation of glutamate uptake and set the stage for research aimed at discovering the molecular mechanisms that couple induction processes to expression processes during learning and memory formation
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