A Critical Role of Neuroligin 2 C-Terminus in OCD and Social Behavior

Neurodevelopmental and neuropsychiatric disorders such as autism and schizophrenia are devastating brain illnesses that are often associated with deficits in social behaviors. Thus, understanding the molecular mechanisms contributing to the etiology underlying these social defects will be critical in developing therapeutic strategies for these disorders. Here, we have identified a crucial role of carboxyl-terminus (C-tail) of Neuroligin 2 (NL2), a cell adhesion molecule highly enriched at inhibitory synapses, in social behaviors. Indeed, we have found that genetic deletion of NL2 C-tail in mice (StopKI mice) significantly reduces GABAergic synaptic density and inhibitory synaptic transmission in hippocampal CA1 neurons. Importantly, both male and female StopKI mice also manifest elevated obsessive-compulsive disorder (OCD)-like phenotypes. In addition, we have observed impaired social cognition behaviors in these mice that have not been previously observed in NL2 knockout (KO) mice. These data reveal an unappreciated role of the NL2 C-tail in regulating social behaviors and highlights the importance of NL2 C-tail mediated signaling in delineating molecular determinants for neurodevelopmental and neuropsychiatric disorders.<b>Significance Statement</b> Neuroligin 2 (NL2), a cell adhesion molecule enriched at inhibitory synapses, has been implicated in various neuropsychiatric disorders, including anxiety, schizophrenia, and autism. However, the domain-specific contribution of NL2 to the pathogenesis of these disorders remains poorly understood. In this study, we have identified a crucial role for the carboxyl-tail of NL2 in the development of obsessive-compulsive disorder (OCD)-like behavior as well as social behavior. These results highlight the significance of NL2 C-tail-mediated signaling in elucidating the molecular mechanisms underlying neurodevelopmental and neuropsychiatric disorders.