Background: As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 ^−/− mice to investigate their phenotypes of synaptic function and social behaviors. Methods: The creation of Dlgap2 ^−/− mice was facilitated by the recombineering-based method, Cre-loxP system and serial backcross. Reversal learning in a water T-maze was used to determine repetitive behaviors. The three-chamber approach task, resident–intruder test and tube task were performed to characterize the social behaviors of mutant mice. Cortical synaptosomal fraction, Golgi-Cox staining, whole-cell patch electrophysiology and transmission electron microscopy were all applied to investigate the function and structure of synapses in the orbitofrontal cortex (OFC) of Dlgap2 ^−/− mice. Results: Dlgap2 ^−/− mice displayed exacerbated aggressive behaviors in the resident–intruder task, and elevated social dominance in the tube test. In addition, Dlgap2 ^−/− mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. Dlgap2 ^−/− mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC. Conclusions: Our findings clearly demonstrate that Dlgap2 plays a vital role in social behaviors and proper synaptic functions of the OFC. Moreover, these results may provide valuable insights into the neuropathology of autism.

Dravet syndrome (DS) is a genetic disorder caused by a deficit in the Nav1.1 channel, leading to drug-resistant epilepsy. The Nav1.1 channel plays a crucial role in microglial cell activation, and microglia are recognized as key mediators of seizures. In this study, we explored the role of microglia in DS-related epileptogenesis using a knock-in mouse model (Scn1a^E1099X/+) that mimics a subset of DS patients. In these DS mice, we observed a significant downregulation of the Nav1.1 channel in microglia. This channel deficit led microglia to adopt a pro-inflammatory state in their quiescent phase. In the LPS-activated state, microglia predominantly exhibited an intermediate morphology rather than the expected fully activated form. The reduced expression of pro-inflammatory cytokines was detected in microglia following treatment with LPS. Notably, we found a significant decrease in the phagocytic ability of microglia in DS mice. Electrophysiological studies revealed an increased immature synaptic activity in the dentate gyrus in DS mice. The impaired microglial phagocytosis of damaged cells, combined with reduced cytokine secretion, may result in an excess of immature synaptic connections, neuronal hyperexcitation, and the formation of abnormal neural circuits in the hippocampus of Scn1a^E1099X/+ mice. These changes could potentially contribute to mechanisms relevant to epileptogenesis in DS.