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.
Highlights
Synaptic remodeling during neonatal development lies behind neuronal networks refinement and nervous system maturation
At postnatal day 21 (P21), l-NAME-treated rats displayed an increase in both, the number (+ 24.4 ± 3.5%) and linear density (+ 9.2 ± 2.9%) of inhibitory puncta (VGAT-ir) apposed to hypoglossal motor neurons (HMNs) somata, in comparison with animals which received the inactive stereoisomer d-NAME (Fig. 3a–d, Table 1)
We report here that endogenous nitric oxide (NO) tunes excitatory/inhibitory balance in the hypoglossal nucleus (HN) in the P7–P21 early postnatal interval
Summary
Synaptic remodeling during neonatal development lies behind neuronal networks refinement and nervous system maturation. The second postnatal week is a critical period in respiratory network development in the rat, when abrupt neurochemical, metabolic, and physiological changes are evident. In this context, a sudden drop in expression of excitatory and heightened expression of inhibitory neurochemicals at P12–P13 occur in multiple respiratory-related brainstem nuclear groups of the rat including the hypoglossal motor nucleus (HN) (Gao et al 2011). An excitatory/inhibitory imbalance in HMNs occurs during the critical period of postnatal development (P12–P13) (Gao et al 2011). Abnormalities in the normal development of HMNs have been associated with sudden infant death syndrome (Konrat et al 1992; Lavezzi et al 2010) and obstructive sleep apnea (Remmers et al 1978), deciphering molecular partners behind synaptic remodeling in the HN is of clinical relevance
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