Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry

• Published in: Nature communications 2020-07, Vol.11 (1), p.3744-3744, Article 3744
• Main Authors: Cao, Feng, Liu, Jackie J., Zhou, Susan, Cortez, Miguel A., Snead, O. Carter, Han, Jing, Jia, Zhengping
• Format: Article
• Language: English
• Subjects: 13/51; 631/378; 631/378/1689; 631/378/340; 631/378/548; 64/60; 82/1; 82/80; 9/26; 9/74; Action Potentials; Adhesion; Animals; Anxiety - physiopathology; Autism; Behavior, Animal; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Adhesion Molecules, Neuronal - metabolism; Circuits; Convulsions & seizures; Disorders; Electrodes; Electroencephalography; Electromyography; Epilepsy; Epilepsy, Absence - metabolism; Epilepsy, Absence - physiopathology; Ethosuximide; Firing pattern; GABAergic Neurons - metabolism; Humanities and Social Sciences; Intralaminar Thalamic Nuclei - physiopathology; Locomotion; Memory; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Nerve Net - physiopathology; Nerve Tissue Proteins - metabolism; Rodents; Science; Science (multidisciplinary); Seizures; Synapses; Synaptic Transmission; Thalamic reticular nucleus; Thalamus; Thalamus - physiopathology; γ-Aminobutyric acid
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17560-3

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures. The anti-absence seizure drug ethosuximide blocks SWDs and rescues behavioral arrests and social memory impairment in the knockout mice. Restoring GABAergic transmission either by optogenetic activation of the thalamic reticular nucleus (nRT) presynaptic terminals or postsynaptic NLG2 expression in the thalamic neurons reduces the SWDs and behavioral arrests in the knockout mice. These results indicate that NLG2-mediated GABAergic transmission at the nRT-thalamic circuit represents a common mechanism underlying both epileptic seizures and ASD. Neuroligins are postsynaptic cell adhesion molecules that are involved in synapse function and autism spectrum disorder. The authors show that NLG2-mediated GABAergic transmission at the thalamic reticular nucleus-thalamic circuit is a common mechanism underlying epileptic seizures and ASD.