NO/cGMP signalling in hippocampal glutamatergic neurons

The NO/cGMP signaling cascade has been proposed to play a role in long-term potentiation (LTP) and the modulation of synaptic transmission. Nitric oxide is formed enzymatically by NO synthases (NOS); two NOS, the endothelial and neuronal isoform (eNOS, nNOS) produce NO as a signalling molecule. Functionally, NO has been reported to act as a retrograde messenger that is generated postsynaptically to increase the neurotransmitter release presynaptically. The NO effects are mediated by the NO-sensitive guanylyl cyclases (NO-GC), which by the formation of cGMP transduce the NO signal. Two functionally indistinguishable isoforms of the NO-GCs, NO-GC1 and NO-GC2 exist that are expressed in similar amounts in the central nervous system. To elucidate their physiological roles, we generated KO mice in which either one of the isoforms is deleted. Surprisingly, LTP measured in hippocampus and visual cortex was abolished in both KO strains indicating that both NO receptors are required for the induction of LTP. These findings are compatible with a pre- and postsynaptic role of the NO-GCs. In a recent study on the presynaptic glutamate release in the hippocampus of the NO-GC KOs, we were able to show that cGMP formed by NO-GC1 in response to eNOS-derived NO enhances glutamate release via hyperpolarization-activated cyclic nucleotide gated channels. Further studies have to address a possible role of cGMP formed by NO-GC2 postsynaptically in hippocampal glutamatergic neurons.