黑皮质素受体激动剂改善Shank3基因缺陷孤独症模型大鼠行为的机制研究OA

Objective To explore the mechanism by which melanotan-II(MT-II)improves social deficits in a Shank3 gene-deficient autism model.Methods Rats were divided into control and Shank3-deficient model groups(n=18 per group)treated by microinjection of empty or Shank3-interfering lentivirus,respectively,into the right lateral ventricle of neonatal rats.Shank3-deficient rats were further divided randomly into two groups:Shank3+saline(Sh3-Sal)and Shank3+MT-II(Sh3-MT-II)groups(n=9 per group).Similarly,control rats were divided into control+saline(V-Sal)and control+MT-II(V-MT-II)groups(n=9 per group).On day 28,rats in the V-MT-II and Sh3-MT-II groups received intraperitoneal(i.p.)injections of MT-II(3.3 mg/kg),while rats in the V-Sal and Sh3-Sal groups received i.p.saline(3.3 mL/kg).Behavioral changes were assessed using the open-field test,grooming behavior analysis,three-chamber social test,and the Morris water maze test.mRNA and protein expression levels of hypothalamic oxytocin(OXT),OXT receptor(OXTR),and melanocortin receptor 4(MC4R)were detected by reverse transcription-polymerase chain reaction and Western blot,respectively.Results In the three-chamber social test,Sh3-Sal group rats showed no significant social preference compared with the time spent with stranger rat 1(P＞0.05).In contrast,after MT-II intervention,Sh3-MT-II group rats spent significantly longer with stranger rat 2(P＜0.01).In the Morris water maze test,rats in the Sh3-Sal group exhibited significant learning and memory impairments compared with the V-Sal group(P＜0.05),while MT-II intervention significantly improved the learning and memory performance of the Sh3-MT-II group(P＜0.01).The open field and grooming tests revealed that Sh3-Sal group rats spent significantly longer in the peripheral zone of the open field and exhibited increased grooming behavior compared with the V-Sal group(P＜0.01).However,MT-II did not significantly alter the center time or self-grooming behavior compared with the Sh3-Sal group(P＞0.05).mRNA expression levels of OXT,OXTR,and MC4R were significantly higher in the Sh3-MT-II group than in the Sh3-Sal group(P＜0.05,P＜0.01).Hypothalamic OXT protein expression was significantly increased in the Sh3-MT-II group compared with the Sh3-Sal group(P＜0.05),while hypothalamic SHANK3 protein expression was significantly decreased in both the Sh3-Sal and Sh3-MT-II groups compared with the V-Sal group(P＜0.05,P＜0.01),and protein expression levels of OXTR and MC4R showed no significant changes(P＞0.05).Conclusions The melanocortin receptor agonist MT-II may ameliorate social deficits in Shank3-deficient autistic rats by activating the hypothalamic OXT system.This suggests that targeting the OXT/MC4R pathway could be a potential therapeutic strategy for social deficits in patients with autism spectrum disorder.