Species, strain and developmental variations in hippocampal neuronal and endothelial nitric oxide synthase clarify discrepancies in nitric oxide-dependent synaptic plasticity.

Nitric oxide (NO) has been implicated in long-term potentiation (LTP) in pyramidal neurons in cellular area 1 (CA1) of the hippocampus. However, considerable confusion exists about the exact role of NO, and the contribution of the endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) isoforms of NO synthase to NO-dependent LTP (NO-LTP), with results often varying, depending on the organism and experimental paradigm used. Using immunohistochemistry and in situ hybridization, we contrast NO synthase expression and activity in rat, mouse, and human hippocampus. nNOS is prominently expressed in all CA1 pyramidal cells of C57B6 mice and humans, while in rats and SV129 mice, its levels are much lower and restricted to the caudal hippocampus. By contrast, eNOS is restricted to endothelial cells. We observe N-methyl-D-aspartate-dependent citrulline production in pyramidal cells of mouse hippocampus, which is absent in nNOS(Delta/Delta) animals. Finally, we observe robust nNOS expression in human CA1 pyramidal cells.The considerable axial, developmental, strain and species-dependent variations in nNOS expression in CA1 pyramidal neurons can explain much of the variation observed in reports of NO-dependent LTP. Moreover, our data suggest that NO produced by eNOS in endothelial cells may play a paracrine role in modulating LTP.