Mechanisms For The Effects Of Stress On Hippocampal Development And Plasticity:the Role Of Nectins

Early environmental factors interact with genetic background to shape the development and function of brain circuits.Adverse early environment,especially early-life stress,impairs the development and plasticity of neural circuits and serves as a key risk factor for psychiatric disorders.Therefore,it is crucial to unravel the molecular mechanisms underlying the detrimental effects of early-life stress on neural circuits.Our previous studies revealed that early-life stress(ELS)elevated the levels of corticotrophin-releasing hormone(CRH)in the mouse hippocampus,overactivated CRH receptor 1(CRHR1),and lowered the levels of nectin-3 that forms heterophilic adhesion with nectin-1.These alterations resulted in the instability of synaptic structure,retraction of dendrites,elimination of spines and impairments of memory.However,the expression pattern and function of nectin-1 and nectin-3 in control or ELS mice during development are still unclear.Therefore,we combined immunostaining,Golgi staining and behavior testing to examine the mechanisms underlying the effects of early-life stress on hippocampal development and plasticity and the potential involvement of nectins.We found that early-life stress downregulated the levels of nectin-1 and nectin-3 in the entorhinal cortex(EC)and hippocampal CA1,induced circuit-specific dendritic developmental deficits,and impaired learning and memory.Moreover,viral-mediated knockdown of nectin-1,but not nectin-3,in the entorhinal cortex from postnatal day 2 onwards disrupted EC-CA1-dependent memory.In addition,nectin-1 knockdown in EC mimicked the negative effects of early-life stress on the development of EC pyramidal neurons.In summary,our data suggest that early-life stress impairs the development,function and plasticity of EC-CA1 circuits by downregulating nectin-1 in EC.In adulthood,chronic exposure to stressful experiences disrupts synaptic plasticity and cognitive function.Previous studies have shown that perirhinal cortex-dependent object recognition memory is impaired by chronic stress.However,the stress effects on molecular expression and structural plasticity in the perirhinal cortex remain unclear.In this study,we applied the chronic social defeat stress paradigm and measured the mRNA levels of nectin-1,nectin-3 and neurexin-1,three synaptic cell adhesion molecules implicated in the adverse stress effects,in the perirhinal cortex of wild-type and conditional forebrain corticotropin-releasing hormone receptor 1 knockout(CRHR1-CKO)mice.Chronic stress reduced perirhinal nectin-1 mRNA levels in wild-type but not CRHR1-CKO mice.In conditional forebrain corticotropin-releasing hormone overexpression(CRH-COE)mice,perirhinal nectin-1 mRNA levels were also reduced,indicating that chronic stress modulates nectin-1 expression through the CRH-CRHR1 system.Moreover,chronic stress altered dendritic spine morphology in the main apical dendrites and reduced spine density in the oblique apical dendrites of perirhinal layer V pyramidal neurons.Our data suggest that chronic stress disrupts cell adhesion and dendritic spine plasticity in perirhinal neurons,which may contribute to stress-induced impairments of perirhinal cortex-dependent memory.