2. Academic Validation
  3. Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice

Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice

  • Aging Cell. 2024 Jun 2:e14209. doi: 10.1111/acel.14209.
Zhun Wang 1 2 3,  Jinpeng Dong 1 2 3,  Mengxue Zhang 1 2 3,  Sixuan Wang 1 2 3,  Jiangnan Wu 4,  Shengran Wang 5,  Yuan Luo 5,  Yongan Wang 5,  Yiqing Yin 1 2 3
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.
  • 2 Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
  • 3 Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 4 Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
  • 5 State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Sciences, Beijing, China.
PMID: 38825816 DOI: 10.1111/acel.14209
Abstract

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.

Keywords

RhoA/ROCK2; fasudil hydrochloride; perioperative neurocognitive disorder; sevoflurane; α5‐GABAAR.

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