NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(665)

Published: Oct. 5, 2022

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role the regulation of secretion gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that disruption neuronal NO synthase (NOS1) activity underlies some forms hypogonadotropic hypogonadism. Whole-exome sequencing was performed on cohort 341 probands with congenital hypogonadism to identify ultrarare variants NOS1 . identified mutant proteins assessed by their ability promote nitrite and cGMP production vitro. In addition, physiological pharmacological characterization carried out Nos1 -deficient mouse model. five heterozygous loss-of-function mutations six (2%), who displayed additional phenotypes including anosmia, hearing loss, intellectual disability. found be transiently expressed GnRH nose both humans mice, deficiency mice resulted dose-dependent defects sexual maturation as well olfaction, hearing, cognition. inhibition postnatal revealed critical time window during shaped minipuberty maturation. Inhaled treatment at rescued reproductive behavioral mice. summary, lack led associated sensory comorbidities reversed deficits maturation, cognition suggesting potential therapy deficiency.

Language: Английский

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The emerging role of nitric oxide in the synaptic dysfunction of vascular dementia

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(2), P. 402 - 415

Published: Jan. 31, 2024

With an increase in global aging, the number of people affected by cerebrovascular diseases is also increasing, and incidence vascular dementia-closely related to risk-is increasing at epidemic rate. However, few therapeutic options exist that can markedly improve cognitive impairment prognosis dementia patients. Similarly Alzheimer's disease other neurological disorders, synaptic dysfunction recognized as main reason for decline. Nitric oxide one ubiquitous gaseous cellular messengers involved multiple physiological pathological processes central nervous system. Recently, nitric has been implicated regulating plasticity plays important role pathogenesis dementia. This review introduces detail emerging states summarizes diverse effects on different aspects dysfunction, neuroinflammation, oxidative stress, blood-brain barrier underlie progress Additionally, we propose targeting oxide-sGC-cGMP pathway using certain specific approaches may provide a novel strategy

Language: Английский

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Differential Roles of Hypothalamic AVPV and Arcuate Kisspeptin Neurons in Estradiol Feedback Regulation of Female Reproduction

Neuroendocrinology, Journal Year: 2019, Volume and Issue: 110(3-4), P. 172 - 184

Published: Aug. 30, 2019

Mammalian reproductive function includes puberty onset and completion, cyclicity, steroidogenesis, gametogenesis, fertilization, pregnancy, lactation; all are indispensable to perpetuate species. Reproductive cycles critical for providing the hormonal milieu needed follicular development maturation of eggs, but cycles, in themselves, do not guarantee ovulation will occur. Here, we review roles female neuroendocrine two hypothalamic populations that produce neuropeptide kisspeptin, demonstrating distinct maintaining ovulation.

Language: Английский

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Retrograde inhibition by a specific subset of interpeduncular α5 nicotinic neurons regulates nicotine preference

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(49), P. 13012 - 13017

Published: Nov. 20, 2017

Repeated exposure to drugs of abuse can produce adaptive changes that lead the establishment dependence. It has been shown allelic variation in α5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk tobacco In brain, α5-containing nAChRs are expressed at very high levels interpeduncular nucleus (IPN). Here we identified two nonoverlapping + cell populations (α5- Amigo1 and α5- Epyc ) mouse IPN respond differentially nicotine. Chronic nicotine treatment altered translational profile more than 1,000 genes neurons, including neuronal nitric oxide synthase (Nos1) somatostatin (Sst). contrast, expression few was population. We show both SST suppress optically evoked neurotransmitter release from terminals habenular (Hb) neurons IPN. Moreover, vivo silencing but not population eliminates reward, measured using place preference. This loss reward mimicked by shRNA-mediated knockdown Nos1 These findings reveal a proaddiction response chronic which released specific α5+ provide retrograde inhibition Hb-IPN circuit thereby enhance motivational properties

Language: Английский

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Phenotyping of nNOS neurons in the postnatal and adult female mouse hypothalamus

The Journal of Comparative Neurology, Journal Year: 2017, Volume and Issue: 525(15), P. 3177 - 3189

Published: June 3, 2017

Neurons expressing nitric oxide (NO) synthase (nNOS) and thus capable of synthesizing NO play major roles in many aspects brain function. While the heterogeneity nNOS-expressing neurons has been studied various regions, their phenotype hypothalamus remains largely unknown. Here we examined distribution cells nNOS postnatal adult female mouse using immunohistochemistry. In both adults neonates, was restricted to regions involved control bodily functions, such as energy balance reproduction. Labeled were found paraventricular, ventromedial, dorsomedial nuclei well lateral area hypothalamus. Intriguingly, seen only after second week life arcuate nucleus (ARH). The most dense heavily labeled population organum vasculosum laminae terminalis (OV) median preoptic (MEPO), where somata neuroendocrine releasing GnRH controlling reproduction are located. A great proportion nNOS-immunoreactive OV/MEPO ARH express estrogen receptor (ER) α. Notably, almost all ERα-immunoreactive also expressed nNOS. Moreover, use EYFPVglut2 , EYFPVgat GFPGad67 transgenic lines revealed that, like neurons, hypothalamic have a glutamatergic phenotype, except for ARH, which GABAergic. Altogether, these observations consistent with proposed role physiological processes.

Language: Английский

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