Long-term potentiation of synaptic transmission in the hippocampus is a widely used model for studying the synaptic plasticity which underlies learning and memory. Most previous studies have focused on a form of LTP which requires the NMDA type of glutamate receptor. This proposal is to study a form of LTP which does not require NMDA-Rs, but instead requires voltage-dependent calcium channels (VDCCs). In both forms of LTP, calcium entry into postsynaptic neurons, through either NMDA-Rs or VDCCs, is required for induction of the potentiation. While much is known about the subsequent cellular events underlying maintenance of NMDA-R dependent LTP, little is known about the maintenance of NMDA-R independent LTP. It is unclear if cellular processes following induction are shared by the two forms of LTP, or if a distinct set of processes underlies each form of LTP. The major aim of this proposal is to define the signaling pathway leading from the induction of NMDA-R independent LTP, through the maintenance of this LTP. Multiple components of potential signaling pathways will be investigated. These include the ion channels., neurotransmitter receptors, second messengers, and the protein kinase targets of these second messengers. This proposal also aims to determine the roles played by metabotropic glutamate receptors in NMDA-R independent LTP. These roles may include: modulation of LTP induction by regulation of postsynaptic membrane potential, inhibitory interneuronal circuitry, or presynaptic neurotransmitter release, as well as regulation of second messenger systems. These experiments will be done using an in vitro brain slice preparation of rat hippocampus (area CA1). Synaptic transmission and LTP will be monitored by electrophysiological measures (extracellular field potential and whole cell/patch clamp recordings of evoked synaptic responses). Electrophysiological and pharmacological manipulations will be used to test possible components of the signaling pathway for NMDA-R independent LTP.
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