Chemogenetic silencing of the midline and intralaminar thalamus blocks amygdala-kindled seizures

Exp Neurol. 2016 Sep;283(Pt A):404-12. doi: 10.1016/j.expneurol.2016.07.003. Epub 2016 Jul 9.


Temporal lobe epilepsy is the most common form of medically-intractable epilepsy. While seizures in TLE originate in structures such as hippocampus, amygdala, and temporal cortex, they propagate through a crucial relay: the midline/intralaminar thalamus. Prior studies have shown that pharmacological inhibition of midline thalamus attenuates limbic seizures. Here, we examined a recently developed technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), as a means of chemogenetic silencing to attenuate limbic seizures. Adult, male rats were electrically kindled from the amygdala, and injected with virus coding for inhibitory (hM4Di) DREADDs into the midline/intralaminar thalamus. When treated with the otherwise inert ligand Clozapine-N-Oxide (CNO) at doses of 2.5, 5, and 10mg/kg, electrographic and behavioral seizure manifestations were suppressed in comparison to vehicle. At higher doses, we found complete blockade of seizure activity in a subset of subjects. CNO displayed a sharp time-response profile, with significant seizure attenuation seen 20-30min post injection, in comparison to 10 and 40min post injection. Seizures in animals injected with a control vector (i.e., no DREADD) were unaffected by CNO administration. These data underscore the crucial role of the midline/intralaminar thalamus in the propagation of seizures, specifically in the amygdala kindling model, and provide validation of chemogenetic silencing of limbic seizures.

Keywords: Amygdala; CNO; Chemogenetic; DREADD; Kindling; Rat; Seizure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / physiopathology*
  • Analysis of Variance
  • Animals
  • Anticonvulsants / pharmacology
  • Anticonvulsants / therapeutic use
  • Clozapine / analogs & derivatives
  • Clozapine / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Electric Stimulation / adverse effects
  • Evoked Potentials / physiology
  • Intralaminar Thalamic Nuclei / drug effects
  • Intralaminar Thalamic Nuclei / physiology*
  • Kindling, Neurologic / physiology*
  • Male
  • Maze Learning / drug effects
  • Midline Thalamic Nuclei / drug effects
  • Midline Thalamic Nuclei / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / drug therapy*
  • Seizures / etiology


  • Anticonvulsants
  • Clozapine
  • clozapine N-oxide