Postsynaptic NO/cGMP Increases NMDA Receptor Currents via Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Hippocampus

作者：Neitz Angela; Mergia Evanthia; Imbrosci Barbara; Petrasch Parwez Elisabeth; Eysel Ulf T; Koesling Doris^*; Mittmann Thomas

来源：Cerebral Cortex, 2014, 24(7): 1923-1936.

DOI：10.1093/cercor/bht048

• cGMP
• guanylyl cyclase
• HCN channels
• hippocampus
• KO
• NMDA receptor
• NO

The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling cascade participates in the modulation of synaptic transmission. The effects of NO are mediated by the NO-sensitive cGMP-forming guanylyl cyclases (NO-GCs), which exist in 2 isoforms with indistinguishable regulatory properties. The lack of long-term potentiation (LTP) in knock-out (KO) mice deficient in either one of the NO-GC isoforms indicates the contribution of both NO-GCs to LTP. Recently, we showed that the NO-GC1 isoform is located presynaptically in glutamatergic neurons and increases the glutamate release via hyperpolarization-activated cyclic nucleotide (HCN)-gated channels in the hippocampus. Electrophysiological analysis of hippocampal CA1 neurons in whole-cell recordings revealed a reduction of HCN currents and a hyperpolarizing shift of the activation curve in the NO-GC2 KOs associated with reduced resting membrane potentials. These features were mimicked in wild-type (WT) neurons with an NO-GC inhibitor. Analysis of glutamate receptors revealed a cGMP-dependent reduction of NMDA receptor currents in the NO-GC2 KO mice, which was mimicked in WT by HCN channel inhibition. Lowering extracellular Mg2+ increased NMDA receptor currents in the NO-GC2 KO and allowed the induction of LTP that was absent at physiological Mg2+. In sum, our data indicate that postsynaptic cGMP increases the N-methyl-d-aspartate (NMDA) receptor current by gating HCN channels and thereby is required for LTP.

• 出版日期2014-7