Abstract
Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1–NMDAR–EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1−/− mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.
Highlights
Social behaviours contain several processes including social approach, interaction, and recognition memory [1, 2], whichThese authors contributed : Xian-Dong Liu, Peng-Hui Ai
To identify the brain regions responding to the various social stimuli, we introduced a social behavioural paradigm to compare the social interactions of object mice with empty environment, stranger, and littermate, respectively (Fig. 1a), which has been used previously [28, 29]
We measured the expression of c-Fos, an immediate early gene marker for activated neurons upon environmental stimuli, at postnatal week (PW) 3 [30, 31]
Summary
Social behaviours contain several processes including social approach, interaction, and recognition memory [1, 2], which. Genomewide association studies over the past decades shed light on genetic variants of PDZ-binding-related proteins and synaptic glutamate receptors to the social abnormalities in ASDs [18,19,20,21,22]. It remains elusive how these key proteins are organized in the responsive cells for the initial social behaviour during postnatal developmental stage. We further reveal that Lnx functions as a scaffold protein to form a multicomplex by interacting with GluN2B and EphB2 receptors through its first and second PDZ domains respectively, which plays an essential and sufficient role for synaptic function and social memory. Our results reveal a postsynaptic multiprotein complex that mediates the formation of social recognition memory during the developing period
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