Many excitatory synapses in the CNS used glutamate as a neurotransmitter. Glutamate activates two classes of receptor-channel complexes, those that are NMDA sensitive and those that are not NMDA sensitive (the latter are activated by quisqualate and kainate). The NMDA sensitive receptor plays a crucial role in the induction of a long-term change in synaptic strength of an excitatory synapse in the CA1 and CA3 regions of the hippocampus. This change is called Long-Term Potentiation (LPT) and may be related to some types of learning and memory. This project focuses on the postsynaptic side of those excitatory synapses involved in LTP. First we will define the relative contribution of NMDA and non-NMDA sensitive receptors to the generation of the excitatory postsynaptic current by using whole-cell voltage-clamp and patch-clamp single channel current recordings in primary neuronal culture and brain slices. Second, we will evaluate the relative contribution of the two classes of excitatory amino acid receptors after induction of LTP in different hippocampal regions and in neocortex. Single-channel current recordings will help to define the different types of postsynaptic channels by comparison with postsynaptic currents. Third, we will test whether enzymes such as protein kinases, that are involved in second messenger cascades, and Ca2+ -dependent proteases such as calpain, can reproduce the changes in the relative NMDA and non-NMDA contributions of synaptic transmission seen in LTP. Fourth, we will investigate any possible role of the glycine modulatory site located on NMDA receptor domains by using antagonists of this site such as 7-chloro-kynurenic acid during LTP. Finally, we will elucidate the mechanism of action of oxygen free radicals, which are reported to affect LTP, on the two components of the excitatory postsynaptic response.
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