title: Chemogenetic silencing of the midline and intralaminar thalamus blocks amygdala-kindled seizures.
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.
authors.affiliation: Department of Pharmacology & Physiology, Georgetown University School of Medicine, United States.
authors.forename: Evan
authors.initials: E
authors.lastname: Wicker
authors.affiliation: Department of Pharmacology & Physiology, Georgetown University School of Medicine, United States. Electronic address: paf22@georgetown.edu.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Forcelli
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D003024:Clozapine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000009:adverse effects; D005071:Evoked Potentials / Q000502:physiology; D020646:Intralaminar Thalamic Nuclei / Q000187:drug effects / Q000502:physiology*; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D020644:Midline Thalamic Nuclei / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology
chemical_list: D000927:Anticonvulsants; D003024:Clozapine; C079149:clozapine N-oxide
keywords: Amygdala; CNO; Chemogenetic; DREADD; Kindling; Rat; Seizure