Roles of the postsynaptic adhesion molecule NGL-2 in the regulation of synaptic plasticity and behavior

Abstract

NGL-2/Lrrc4 is one of the postsynaptic adhesion molecules that contains leucine rich repeats (LRRs), a shared feature of LRR proteins such as LTRRM and SALM. NGL-2 intracellularly interacts with the postsynaptic scaffolding protein PSD-95 and trans-synaptically binds to the presynaptic adhesion molecule Netrin-G2. Previous studies have reported that NGL-2 is expressed in a layer-specific manner in the brain and regulates diverse neurophysiological functions including excitatory synapse development and synaptic transmission. Moreover, recent bioinformatics studies of neuropsychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia have strongly associated mutations of NGL2/LRRC4 in these diseases through approaches including whole exome and genome sequencing. The function of NGL-2, however, remains largely unknown from the behavioral and physiological perspectives. Here, my study show that NGL-2 regulates NMDA receptor-dependent synaptic transmission and plasticity and social and repetitive behaviors based on the data from Ngl$2^{-/-}$ mice that lack NGL-2 proteins. The defects in social interaction and repetitive behaviors, two core symptoms of ASD, were successfully rescued by the partial NMDA receptor agonist D-cycloserine. In addition, D-cycloserine improved abnormal NMDAR function and synaptic plasticity in these mice. Together, my study has found novel functions of NGL-2 in regulating NMDAR receptors, a core component of excitatory synaptic transmission, and critical brain function including sociability, cognition, and learning and memory. This study also highlights the importance of NGL-2 in neuropsychiatric disorders, and suggests abnormal NMDAR function might represent a therapeutic target for related disorders.