The objectives of the work are to establish the role of ATP in synaptic neurotransmission and synaptic efficiency in the CNS. These studies will be conducted on hippocampal and striatal slices. We recently found a calcium-dependent release of ATP from presynaptic terminals following intense stimulation of Schaffer collaterals (Sch.coll.) in vitro. High frequency stimulation which evokes ATP release simultaneously induced permanent changes in the synaptic efficiency. This phenomenon, called long-term potentiation (LTP), is generally accepted as a good model for testing the properties of memory. Exogenous ATP applied to the hippocampal slices at the concentration observed in the release experiments(nM range) permanently enhanced synaptic efficiency. My hypothesis is that ATP release during intense stimulation triggers changes involved in LTP and may be related to memory formation. The present study will concentrate on two problems : A/further characterization of ATP release mechanism, and B/ the mechanism, through which ATP can potentiate synaptic response. I will determine if the synapses which use different transmitters and have different ability to show LTP (striatal neurons versus hippocampal neurons), release ATP in a similar way. In order to better characterize the metabolism of release ATP, inhibitors and antibody towards ecto-Ca2+- ATPase (the main enzyme responsible for the ATP breakdown in the extracellular space) will be used. In addition, biochemical studies will be conducted to determine if biochemical events observed after electrically evoked LTP evoked potentiation. These studies will be correlated with electrophysiological recordings. The calcium accumulation, release and uptake of endogenous glutamate will be evaluated in the slices incubated with different ATP concentrations. Kinase C regulated by products of phosphoinositol hydrolysis is according to current concepts, a key enzyme engaged in LTP. A suggestion that released ATP can induce LTP by modifying the kinase C activity will be tested. The effect of ATP on synaptic potentials will help find the role of ATP in molecular mechanism of synaptic plasticity and memory.
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