Nectin-3 Modulates The Structural Plasticity Of Dentate Granule Cells And The Cognitive Effects Of Early-life Stress

Nectin-3,a cell adhesion molecule enriched in hippocampal neurons,is important for dendritic spine remodeling and implicated in stress-induced cognitive deficits.Up to now,it remains unclear whether disrupted nectin-3-mediated cell adhesion in the dentate gyrus(DG)mediates the effects of early-life stress on the structural plasticity of DG neurons and hippocampus-dependent memory.In this study,we found that DG nectin-3 levels were developmentally regulated and reduced by early postnatal stress exposure in adult mice.Suppression of nectin-3 levels in all DG neuron populations by adeno-associated virus(AAV)recapitulated the cognitive effects of early-life stress,and impaired long-term spatial memory and temporal order memory.Moreover,AAV-mediated DG nectin-3 knockdown increased the number of doublecortin-immunoreactive differentiating cells under the proliferative stage,but markedly decreased DG calbindin immunoreactivity,indicating that nectin-3 may modulate the differentiation and maturation of adult-born DG granule cells.Next,we used retrovirus to selectively reduce nectin-3 levels in newly generated DG neurons and noticed that nectin-3 knockdown in new DG neurons also impaired long-term spatial memory.In addition,suppressing nectin-3 expression in new DG neurons evoked a reduction of the density of spines,especially thin spines.These results indicate that nectin-3 expressed in DG neurons may modulate adult neurogenesis,dendritic spine plasticity and the cognitive effects of early-life stress.