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

Feng Cao,Zhengping Jia,Jackie J Liu,Jing Han,Susan Zhou,O Carter Snead,Miguel A Cortez

doi:10.1038/s41467-020-17560-3

Abstract

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.

Highlights

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms
We show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures
We further demonstrate that these seizures and behavioral deficits are associated with impaired GABAergic transmission in the thalamic neurons and can be alleviated by activating the thalamic reticular nucleus projection to the ventrobasal thalamus

Summary

Introduction

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. A utism spectrum disorders (ASD) are a class of life-long neurodevelopmental disorders characterized by deficits in social behavior and communication, repetitive behaviors, and restricted interests[1,2,3] In addition to these symptoms, ASD exhibit high rates of comorbidity with other abnormalities such as increased seizures, depression, anxiety, and sleep problems[4,5,6,7,8]. Animal models of NLGs display autistic-like behaviors including impaired social interaction, vocal communication, and cognition[24,25,26] These results indicate that abnormal NLG function is a causal factor for ASD phenotypes, but whether dysregulated NLGs are involved in the pathogenic process of epileptic seizures remains unclear. Several studies suggest that Neuroligin 2 (NLG2) may be important in linking ASD with increased seizures

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