NRG1-ErbB4信号介导的NMDA受体紊乱在七氟醚神经毒性中的作用和机制研究

GABA受体激动剂七氟醚是临床常用的全麻药，已报道其可损害胎儿大脑发育。我们及前人的研究发现，胚胎期七氟醚暴露致出生后大脑NMDA受体及PSD95表达异常，树突发育障碍。但胚胎期NMDA受体表达和组配尚不完善，是什么机制介导了七氟醚对出生后NMDA受体的调控尚不清楚。我们进一步发现，胎脑GABA合成酶GAD67的下调及其调控因子NRG1的上调，有报道NRG1-ErbB4信号也参与调控NMDA受体,其下游PSD95/Kalirin-7是树突发育的重要调节信号。据此我们推测：七氟醚可能通过NRG1-ErbB4信号调控NMDA受体功能，致下游PSD95/Kalirin-7信号异常阻碍树突发育。为此，我们将用ErbB4条件性敲除动物模型、行为学、分子生物学等方法验证NRG1-ErbB4信号介导的NMDA受体紊乱及树突发育异常是七氟醚神经毒性的重要分子机制。为全麻药毒性机制及干预靶点提供理论依据。

GABA mimetic sevoflurane is a commonly used anaesthetic for pregnant women. It can damage fetal brain development. Previous studies including ours found that sevoflurane exposure in the embryonic period can cause abnormal NMDA receptor and the anchor protein PSD95 expression, and impair the dendritic development in the brain after birth. How sevoflurane affects NMDA receptor expression and formation at embryonic period remains unknown although our preliminary data showed that sevoflurane exposure can cause downregulation of GABA synthase GAD67 and upregulation of its regulatory factor neuregulin 1(NRG1) in fetal brain. Furthermore, NRG1-ErbB4 signaling was reported to be involved in NMDA receptor regulation and the PSD95/Kalirin-7 is considered to an important downstream signaling regulation for dendritic development. Accordingly, we proposed that sevoflurane may modulate GABA coupled with NMDA receptor function through NRG1-ErbB4 signaling, cause downstream PSD95/Kalirin-7 signal abnormality and then impaire dendritic development. We will treat conditional ErbB4 knockout animals with sevoflurane and assess their behavioral and its associated molecular changes to address the role of of NRG1-ErbB4 signal mediated NMDA receptors’ abnormality in sevoflurane induced abnormal dendritic development. The outcome from the proposed application is likely to provide the theoretical basis for the anesthetic-induced neurotoxicity for identifying therapeutic targets.