Postnatal nectin-3 knockdown induces structural abnormalities of hippocampal principal neurons and memory deficits in adult mice

The early postnatal stage is a critical period of hippocampal neurodevelopment and also a period of high vulnerability to adverse life experiences. Recent evidence suggests that nectin-3, a cell adhesion molecule, mediates memory dysfunction and dendritic alterations in the adult hippocampus induced by postnatal stress. But it is unknown whether postnatal nectin-3 reduction alone is sufficient to alter hippocampal structure and function in adulthood. Here, we down regulated hippocampal expression of nectin-3 and its heterophilic adhesion partner nectin-1, respectively, from early postnatal stage by injecting adeno-associated virus (AAV) into the cerebral lateral ventricles of neonatal mice (postnatal day 2). We found that suppression of nectin-3, but not nectin-1, expression from the early postnatal stage impaired hippocampus-dependent novel object recognition and spatial object recognition in adult mice. Moreover, AAV-mediated nectin-3 knockdown significantly reduced dendritic complexity and spine density of pyramidal neurons throughout the hippocampus, whereas nectin-1 knockdown only induced the loss of stubby spines in CA3. Our data provide direct evidence that nectins, especially nectin-3, are necessary for postnatal hippocampal development of memory functions and structural integrity.