Nitrergic modulation of neuronal excitability in the mouse hippocampus is mediated via regulation of Kv2 and voltage‐gated sodium channels

Scheiblich, Hannah; Steinert, Joern R.

Abstract

Regulation of neuronal activity is a necessity for communication and information transmission. Many regulatory processes which have been studied provide a complex picture of how neurons can respond to permanently changing functional requirements. One such activity-dependent mechanism involves signaling mediated by nitric oxide (NO). Within the brain, NO is generated in response to neuronal NO synthase (nNOS) activation but NO-dependent pathways regulating neuronal excitability in the hippocampus remain to be fully elucidated. This study was set out to systematically assess the effects of NO on ion channel activities and intrinsic excitabilities of pyramidal neurons within the CA1 region of the mouse hippocampus. We characterized whole-cell potassium and sodium currents, both involved in action potential (AP) shaping and propagation and determined NO-mediated changes in excitabilities and AP waveforms. Our data describe a novel signaling by which NO, in a cGMP-independent manner, suppresses voltage-gated Kv2 potassium and voltage-gated sodium channel activities, thereby widening AP waveforms and reducing depolarization-induced AP firing rates. Our data show that glutathione, which possesses denitrosylating activity, is sufficient to prevent the observed nitrergic effects on potassium and sodium channels, whereas inhibition of cGMP signaling is also sufficient to abolish NO modulation of sodium currents. We propose that NO suppresses both ion channel activities via redox signaling and that an additional cGMP-mediated component is required to exert effects on sodium currents. Both mechanisms result in a dampened excitability and firing ability providing new data on nitrergic activities in the context of activity-dependent regulation of neuronal function following nNOS activation.

Citation

Scheiblich, H., & Steinert, J. R. (2021). Nitrergic modulation of neuronal excitability in the mouse hippocampus is mediated via regulation of Kv2 and voltage‐gated sodium channels. Hippocampus, 31(9), 1020-1038. https://doi.org/10.1002/hipo.23366

• Journal Article Type: Article
• Acceptance Date: May 7, 2021
• Online Publication Date: May 28, 2021
• Publication Date: 2021-09
• Deposit Date: Jan 18, 2023
• Publicly Available Date: Jan 18, 2023
• Journal: Hippocampus
• Print ISSN: 1050-9631
• Electronic ISSN: 1098-1063
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 31
• Issue: 9
• Pages: 1020-1038
• DOI: https://doi.org/10.1002/hipo.23366
• Keywords: Cognitive Neuroscience
• Public URL: https://nottingham-repository.worktribe.com/output/12902113
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/hipo.23366