Format

Send to

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

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

Author information

1
Department of Pharmacology & Physiology, Georgetown University School of Medicine, United States.
2
Department of Pharmacology & Physiology, Georgetown University School of Medicine, United States. Electronic address: paf22@georgetown.edu.

Abstract

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

PMID:
27404844
PMCID:
PMC4992629
DOI:
10.1016/j.expneurol.2016.07.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center