Nitric oxide controls excitatory/inhibitory balance in the hypoglossal nucleus during early postnatal development

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ORIGINAL ARTICLE

Nitric oxide controls excitatory/inhibitory balance in the hypoglossal nucleus during early postnatal development Federico Portillo1   · Bernardo Moreno‑López1  Received: 10 July 2020 / Accepted: 17 October 2020 © The Author(s) 2020

Abstract Synaptic remodeling during early postnatal development lies behind neuronal networks refinement and nervous system maturation. In particular, the respiratory system is immature at birth and is subjected to significant postnatal development. In this context, the excitatory/inhibitory balance dramatically changes in the respiratory-related hypoglossal nucleus (HN) during the 3 perinatal weeks. Since, development abnormalities of hypoglossal motor neurons (HMNs) are associated with sudden infant death syndrome and obstructive sleep apnea, deciphering molecular partners behind synaptic remodeling in the HN is of basic and clinical relevance. Interestingly, a transient expression of the neuronal isoform of nitric oxide (NO) synthase (NOS) occurs in HMNs at neonatal stage that disappears before postnatal day 21 (P21). NO, in turn, is a determining factor for synaptic refinement in several physiopathological conditions. Here, intracerebroventricular chronic administration (P7–P21) of the broad spectrum NOS inhibitor l-NAME (N(ω)-nitro-l-arginine methyl ester) differentially affected excitatory and inhibitory rearrangement during this neonatal interval in the rat. Whilst l-NAME led to a reduction in the number of excitatory structures, inhibitory synaptic puncta were increased at P21 in comparison to administration of the inactive stereoisomer d-NAME. Finally, l-NAME decreased levels of the phosphorylated form of myosin light chain in the nucleus, which is known to regulate the actomyosin contraction apparatus. These outcomes indicate that physiologically synthesized NO modulates excitatory/inhibitory balance during early postnatal development by acting as an anti-synaptotrophic and/or synaptotoxic factor for inhibitory synapses, and as a synaptotrophin for excitatory ones. The mechanism of action could rely on the modulation of the actomyosin contraction apparatus. Keywords  Nitric oxide · Synaptic refinement · VGAT​ · VGLUT2 · Myosin light chain · Synaptotoxin · Synaptotrophin

Introduction Synaptic remodeling during neonatal development lies behind neuronal networks refinement and nervous system maturation. The adjustment and/or removal of existing synapses and the generation of new synapses are the substratum for synaptic reorganization occurring in learning, memory formation, and refinement of sensorimotor functions (Benson * Federico Portillo [email protected] * Bernardo Moreno‑López [email protected] 1



Grupo de Neurodegeneración y Neurorreparación (GRUNEDERE) and Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Plaza Falla 9, 11003 Cádiz, Spain

et al. 2001; Sunico et al. 2005). At the neonatal stage, redundant synaptic connections are transiently formed. Once