Hopper, R.A.; (2006) Nitric oxide and hippocampal synaptic plasticity. Doctoral thesis , University of London.

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Abstract

Nitric oxide (NO) functions widely as a signalling molecule in the brain and has been implicated in several types of synaptic plasticity, including NMDA receptor-dependent long-term potentiation (LTP) in the hippocampus. The precise role played by NO in this and related phenomena is uncertain and the aim of my research was to explore this question. The principal receptor for NO possesses guanylyl cyclase activity, so that NO binding results in cGMP formation. NO has also been claimed to modify thiol residues (S'-nitrosation) and, through this mechanism, exert a negative feedback on NMDA receptors. Tests of this hypothesis were conducted by recording NMDA receptor-mediated field excitatory postsynaptic potentials in the CA1 region of rat hippocampal slices. Neither manipulation of endogenous NO levels nor application of exogenous NO had any effect. The reported inhibition of synaptic NMDA receptor function when NO is released by UV light from a caged derivative was confirmed, but a similar result was obtained using a combination of exogenous NO and UV light, casting doubt on the physiological relevance this effect. There has been debate over the isoform of NO synthase (endothelial, neuronal, or both) needed for hippocampal LTP and it has been suggested that LTP requires not only a phasic NO signal associated with tetanic stimulation but also a tonic level of NO. cGMP measurements in hippocampal slices indicated that endothelial NO synthase was largely responsible for the basal NO tone, and that T-type voltage-gated calcium channels may elicit the steady output of NO, presumably from endothelial cells. Electrophysiological tests conducted in CA1 found a deficit in LTP both in eNOS-deficient mice and in wild type mice subjected to selective nNOS inhibition. The results indicate that both isoforms of NO synthase participate in LTP but may perform distinct roles.

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