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Nitric oxide signalling in hippocampal synaptic plasticity

Pigott, BM; (2012) Nitric oxide signalling in hippocampal synaptic plasticity. Doctoral thesis, UCL (University College London). Green open access

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Abstract

Nitric oxide (NO) is a freely diffusible transmitter acting throughout the mammalian nervous system via guanylyl cyclase activation and cGMP production. Since neuronal NO synthesis is linked to NMDA receptor activation, much research has focused on the role of NO in NMDA receptor-dependent long-term potentiation (LTP). The proposed role predicts that exogenous NO, paired with a standard LTP induction protocol, should restore the NO-dependent component of LTP when NMDA receptors are blocked. Surprisingly, however, tests of this prediction have not been reported. Here, it was found that exogenous NO, paired with a 1-s, 100-Hz tetanus during NMDA receptor blockade yielded a slowly-rising, long-lasting potentiation of CA1 field EPSPs in hippocampal slices. Like NO-dependent LTP, this potentiation required the tetanus and was guanylyl cyclase-dependent. Contrary to predictions, however, the NO-induced potentiation was additive with subsequent LTP. At CA1 and other synapses, NO is viewed as a putative retrograde transmitter, generated postsynaptically and acting presynaptically. Discordant with this role, the NO-induced potentiation was not associated with a persistent change in paired-pulse facilitation, an index of presynaptic function. However, endogenous NO did appear to facilitate neurotransmitter release under conditions of basal stimulation. In this case, NO generated by endothelial cells was responsible, perhaps explaining the requirement for endothelium-derived NO in LTP. An NMDA receptor-independent form of LTP involving L-type voltage-gated Ca2+ channels has previously been described at CA1 synapses. Unexpectedly, we found that this type of LTP also required NO, apparently derived solely from neurons. Unfortunately, supposed inhibitors of neuronal NO synthesis, though widely used, were found to be inadequately selective to be of use diagnostically. Finally, presynaptic effects of NO, such as those described above, have been reported to require the guanylyl cyclase α1 subunit. Accordingly, immunohistochemistry was used to investigate the location of this subunit in the hippocampus.

Type:Thesis (Doctoral)
Title:Nitric oxide signalling in hippocampal synaptic plasticity
Open access status:An open access version is available from UCL Discovery
Language:English
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Wolfson Inst for Biomedical Research

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