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Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5‐GABAAR, a γ‐aminobutyric acid type A receptor (GABAAR) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p‐radixin and α5‐GABAAR was observed. To inhibit ROCK2 activity, either an adeno‐associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5‐GABAAR. Moreover, the colocalization of α5‐GABAAR and p‐radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5‐GABAAR and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5‐GABAAR is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function. [ABSTRACT FROM AUTHOR]

Background: Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5‐GABAAR. Methods: Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%–3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL‐6 24 h post‐anesthesia. Western blot and RT‐PCR were performed to measure the levels of α5‐GABAAR, Radixin, P‐ERM, P‐Radixin, Gephyrin, IL‐6, and ROCK. The spatial distribution and expression of α5‐GABAAR on neuronal somata were analyzed using histological and three‐dimensional imaging techniques. Results: MWM test indicated that partial long‐term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL‐6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5‐GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5‐GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5‐GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra‐synaptic space, the expression level of α5‐GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. Conclusion: Dysregulated α5‐GABAAR expression and distribution contributes to sevoflurane‐induced partial long‐term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies. [ABSTRACT FROM AUTHOR]

Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5-GABA A R, a γ-aminobutyric acid type A receptor (GABA A R) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p-radixin and α5-GABA A R was observed. To inhibit ROCK2 activity, either an adeno-associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5-GABA A R. Moreover, the colocalization of α5-GABA A R and p-radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5-GABA A R and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5-GABA A R is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function., (© 2024 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Objective: To explore the genetic basis for a family with non-syndromic autosomal recessive deafness., Methods: The proband and her parents were subjected to physical and audiological examinations. With genomic DNA extracted from peripheral blood samples, next-generation sequencing was carried out using a panel for deafness genes. Suspected mutation was validated by Sanger sequencing and qPCR analysis of her parents., Results: The proband presented bilateral severe sensorineural hearing loss at three days after birth. Her auditory threshold was 110-120 dBnHL but with absence of vestibular and retinal symptoms. Her brother also had deafness but her parents were normal. No abnormality was found upon physical examination of her family members, while audiological examination showed no middle ear or retrocochlear diseases. Next-generation sequencing identified compound heterozygous mutations of the MYO7A gene, including a previously known c.462C>A (p. Cys154Ter) and a novel EX43_46 Del, which were respectively derived from her mother and father., Conclusion: The compound heterozygous mutations of the MYO7A gene probably underlie the disease in this family. Our findings has enriched the mutation spectrum for non-syndromic autosomal recessive deafness 2.