• Qi Wang, Evanthia Mergia, Doris Koesling, and Thomas Mittmann.
• Institute of Physiology, UMC of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128 Mainz, Germany.
• Neuroscience. 2017 Sep 30; 360: 180-189.

AbstractIn hippocampus, two guanylyl cyclases (NO-GC1 and NO-GC2) are involved in the transduction of the effects of nitric oxide (NO) on synaptic transmission. However, the respective roles of the NO-GC isoforms on synaptic transmission are less clear in other regions of the brain. In the present study, we used knock-out mice deficient for the NO-GC1 isoform (NO-GC1 KO) to analyze its role in the glutamatergic and GABAergic neurotransmission at pyramidal neurons in layers II/III of somatosensory cortex. NO-GC1 KO slices revealed reduced frequencies of miniature excitatory- and inhibitory-postsynaptic currents, increased paired-pulse ratios and decreased input-output curves of evoked signals, which indicated the reduction of glutamate and GABA release in NO-GC1 KO mice. The functional changes in NO-GC1 KO mice were caused by the lack of cGMP as they were rescued to WT-like levels by the cGMP analog, 8-Br-PET-cGMP and conversely, mimicked by the NO-GC inhibitor, ODQ, in WT slices. In search of a cGMP target, two blockers of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (ZD7288 and DK-AH269) reduced glutamate release in WT to the level of NO-GC1 KO mice suggesting HCN channels as possible effectors for presynaptic cGMP enhancing the glutamate release probability. By blocking postsynaptic NMDA receptors, the NMDA receptor-dependent NO signal was shown to be linked to the effect of NO-GC1 on presynaptic GABA release. Of note, the balance between glutamatergic and GABAergic inputs at individual synapses remained unaltered in the NO-GC1 KO mice. In sum, our results indicate a role for cGMP generated by presynaptic localized NO-GC1 to adjust inhibitory and excitatory inputs at individual synapses in the somatosensory cortex.Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

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