Max Planck Institute of Psychiatry, Munich, Germany.
Nat Neurosci. 2013 Jun;16(6):706-13. doi: 10.1038/nn.3395. Epub 2013 May 5.
Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.
应激通过促肾上腺皮质激素释放激素受体 1（CRHR1）损害认知，但异常的 CRHR1 信号与应激引起的认知障碍之间的分子联系尚不清楚。我们研究了细胞黏附分子 nectin-3 是否是 CRHR1 对认知和结构重塑的影响所必需的，这种影响发生在早期生活压力暴露之后。出生后应激的成年小鼠海马 nectin-3 水平降低，这种降低可以被 CRHR1 失活所减弱，也可以被前脑神经元中促肾上腺皮质激素释放激素（CRH）的过表达所模拟。急性应激会动态降低海马 nectin-3 水平，这涉及到 CRH-CRHR1，但不涉及糖皮质激素受体信号。抑制海马 nectin-3 会导致空间记忆缺陷和树突棘丢失，而增强海马 nectin-3 的表达则可以挽救早期生活应激对成年后记忆和树突棘密度的不利影响。我们的研究结果表明，海马 nectin-3 是应激对记忆和结构可塑性影响所必需的，表明 CRH-CRHR1 系统与 nectin-afadin 复合物相互作用，介导这种影响。
