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

Nat Commun. 2020 Jul 27;11(1):3744. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Anxiety / physiopathology
  • Behavior, Animal*
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • Electrodes
  • Electroencephalography
  • Electromyography
  • Epilepsy, Absence / metabolism*
  • Epilepsy, Absence / physiopathology*
  • Ethosuximide
  • GABAergic Neurons / metabolism*
  • Intralaminar Thalamic Nuclei / physiopathology
  • Locomotion
  • Memory
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / physiopathology*
  • Nerve Tissue Proteins / metabolism*
  • Synaptic Transmission*
  • Thalamus / physiopathology*

Substances

  • Cell Adhesion Molecules, Neuronal
  • Nerve Tissue Proteins
  • neuroligin 2
  • Ethosuximide