Impaired cortico-striatal excitatory transmission triggers epilepsy

Nat Commun. 2019 Apr 23;10(1):1917. doi: 10.1038/s41467-019-09954-9.

Abstract

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anticonvulsants / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Dioxoles / pharmacology
  • Electroencephalography
  • Epilepsy, Absence / drug therapy
  • Epilepsy, Absence / genetics
  • Epilepsy, Absence / metabolism
  • Epilepsy, Absence / physiopathology
  • Ethosuximide / pharmacology
  • Gene Expression Regulation
  • Haploinsufficiency
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Interneurons / pathology
  • Mice
  • Mice, Knockout
  • Munc18 Proteins / deficiency
  • Munc18 Proteins / genetics*
  • NAV1.2 Voltage-Gated Sodium Channel / deficiency
  • NAV1.2 Voltage-Gated Sodium Channel / genetics*
  • Neocortex / drug effects
  • Neocortex / metabolism*
  • Neocortex / pathology
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Piperidines / pharmacology
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism
  • Seizures / genetics*
  • Seizures / metabolism
  • Seizures / physiopathology
  • Seizures / prevention & control
  • Signal Transduction
  • Synaptic Transmission*
  • Thalamus / drug effects
  • Thalamus / metabolism

Substances

  • 1-(quinoxalin-6-ylcarbonyl)piperidine
  • Anticonvulsants
  • Dioxoles
  • Munc18 Proteins
  • NAV1.2 Voltage-Gated Sodium Channel
  • Piperidines
  • Receptors, AMPA
  • Stxbp1 protein, mouse
  • Ethosuximide