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The overall goal of this proposal is to address the role of
glutamate transporters on memory mechanisms. While most
studies of memory mechanisms focus on either hippocampal
presynaptic transmitter release or postsynaptic receptors,
few have characterized the role of glutamate transporters in
modulating synaptic efficacy in this structure.
Interestingly, one study found increases in glutamate
transporter mRNA at the Schaffer collateral-CA1 hippocampal
pathway following long-term potentiation (LTP) and fear
conditioning (Levenson et al., 2002). While this increase in
glutamate transporter expression immediately following LTP
is understandable (to clear excess glutamate following LTP),
the increase following contextual fear conditioning is not
as clear. It seems more probable that contextual fear
learning would elicit a down-regulation of glutamate
transporter, in order to augment synaptic efficacy in the
hippocampus. In fact, work performed while I was a postdoc
at the Univ. of Texas at San Antonio, found an increase of
the glutamate transporter GluT mRNA 1 hr after LTP at the
opioid-dependent mossy fiber-CA3 pathway, and a decrease of
the same transporter following spatial learning of a water
maze. Due to its location and connectivity, the mossy fiber
projection to CA3 is considered a major player in the
processing of contextual memories, yet little is known
regarding the role of glutamate clearance at this synapse.
Our previous work suggests that glutamate transporters exert
a regulatory role in mossy fiber plasticity. In this
proposal, we will further assess the role of specific
neuronal and glial glutamate transporters on mossy fiber
plasticity following in vivo LTP and hippocampal learning by
isolating the pre and post-synaptic components of the mossy
fiber synapse using laser capture microdissection (LCM). In
Specific Aim 1, we will determine if glutamate transporters
increase on glia and neurons at the mossy fiber synapse of
the hippocampus following mossy fiber-CA3 long term
potentiation in vivo. In Specific Aim 2, we will determine
if neuronal and/or glial glutamate transporters are
down-regulated at the mossy fiber synapse following spatial
learning on a Morris water maze. The central hypothesis is
that glutamate transporters exert a modulatory role at the
mossy fiber synapse during LTP and learning. Understanding
the modulation in hippocampal plasticity could lead to
interventions to augment hippocampal functioning in
memory-related disorders.
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