Astrocytic adrenergic α2 receptor contributes to the mechanisms underlying the circadian rhythmicity of seizure susceptibility

Clozapine N-oxide (CNO) at a dose of 0.5 mg/kg elicited significantly more severe seizures during the light phase compared with the dark phase.

• Circadian patterns in seizure susceptibility have been observed in patients with epilepsy.
• Chemogenetic activation of the Gi pathway in hippocampal astrocytes reduced mild seizure occurrences specifically during the light phase.
• Knockdown of adrenergic α2 receptors in astrocytes increased seizure susceptibility during the light phase, while administration of an α2 agonist partially reversed this effect.
• Atipamezole, an α2 antagonist, enhanced lactate production in astrocytes, indicating a potential link between adrenergic signaling and metabolic responses.
• Supplementing with medium-chain fatty acids in epileptic mice mitigated seizure exacerbation caused by α2 receptor knockdown, likely due to the production of ketone bodies.

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