<p>Circadian rhythmicity in seizure susceptibility has been documented in patients with epilepsy. We established a chemogenetic epilepsy model induced using Gq-coupled designer receptors exclusively activated by designer drugs to examine the mechanisms underlying the circadian rhythmicity of seizure susceptibility. Intraperitoneal administration of clozapine N-oxide (CNO) induced dose-dependent seizure behaviors characteristic of mild (Racine scale III or less) and severe (Racine scale IV–V) seizures. CNO at a dose of 0.5 mg/kg elicited significantly more severe seizures during the light phase (Zeitgeber time 3 [ZT 3]) compared with the dark phase (ZT 15). Chemogenetic activation of the Gi instead of the Gq pathway in hippocampal astrocytes suppressed the number of mild seizures exclusively during the light phase. Astrocyte-specific knockdown of adrenergic α2 but not α1 or β receptors exacerbated seizure susceptibility specifically in the light phase, an effect partially reversed by administration of 0.2 mg/kg of dexmedetomidine, an adrenergic α2 agonist. The administration of atipamezole, an α2 antagonist, significantly upregulated norepinephrine-induced lactate production in both intra- and extra-cellularly cultured astrocytes. Supplementation with medium-chain fatty acids in epileptic mice rescued astrocytic α2 receptor knockdown-induced seizure exacerbation, which produce blood–brain-barrier-permeable ketone bodies that likely balance the pro-epileptic lactate burden. Taken together, these findings suggest that astrocytic adrenergic α2 signaling at least partly mediates circadian rhythmicity in seizure susceptibility.</p>