Neuroligin 1 regulates autistic-like repetitive behavior through modulating the excitability of striatal D2 expressing medium spiny neurons

Autism Spectrum Disorder (ASD) is a neurological condition characterized by social deficits and restricted and repetitive behaviors (RRBs) as the primary symptoms. These traits pose a significant risk to individuals' health and are becoming more common. However, the specific cellular and neural circuit mechanisms leading to these abnormal behaviors are not yet clear. Here, we report that the absence of the ASD-related protein Neuroligin 1 (NLG1) leads to an increase in self-grooming and digging time and frequency in mice. Inhibition of NLG1 expression in the medium spiny neurons (D2-MSN) that express dopamine receptor D2 in the dorsal striatum is associated with the RRB phenotypes. Next, we discover that the NLG1-deficient D2-MSN is hyperactivated, which is correlated with the excessive self-grooming and digging behaviors of mice. Inhibiting the activity of D2-MSN reduces the time and frequency of these RRBs. Furthermore, we demonstrate that the generation of self-grooming behavior relies on rapid silencing following high-frequency D2-MSN activity, whereas the digging behavior depends on the accumulation effect following D2-MSN activity. Finally, we reveal that the overactivated PKC in NLG1-deficient mice contributes to excessive repetitive behaviors and neuronal excitability. In this study, we investigate the molecular and cellular processes by which NLG1 influences RRBs and propose potential mechanisms for the generation of self-grooming and digging behavior, as well as suggest potential treatments and interventions for ASD.