Mice deficient in endothelial nitric oxide synthase exhibit a selective deficit in hippocampal long-term potentiation

Long-term potentiation, a persistent increase in synaptic efficacy, may req uire a retrograde signal originating in the postsynaptic cell that induces an increase in presynaptic neurotransmitter release. We have constructed a mouse homozygous for a targeted null mutation in the endothelial isoform of nitric oxide synthase and report that long-term potentiation in the CA1 re gion of these mice is entirely absent under weak stimulation conditions. Ap plication of a membrane-permeant guanosine-3',5'-cyclic monophosphate analo gue during tetanus fails to compensate for this deficit, suggesting that ni tric oxide produced by endothelial nitric oxide synthase may affect long-te rm potentiation through a cascade that does not include guanylyl cyclase. W e also report that strong tetanic stimulation can induce robust longterm po tentiation in these mice which is not blocked by pharmacological inhibitors of nitric oxide synthase. Furthermore, mice lacking endothelial nitric oxi de synthase show no shift in the frequency-response curve for the induction of long-term potentiation. Basal synaptic transmission, paired-pulse facil itation and the electrical properties of CA1 cells in these mice were simil ar to controls. These results support a selective role for endothelial nitric oxide synthas e in long-term potentiation, but also demonstrate that nitric oxide synthas e is not involved in this process under all conditions. (C) 1999 IBRO. Publ ished by Elsevier Science Ltd.