β‐Hydroxybutyrate reduces neuronal excitability via GIRK channels

Résumé fourni par la source

OBJECTIVE: The ketogenic diet is used to treat drug-resistant epilepsy, yet the molecular mechanisms coupling metabolic state to seizure suppression remain understudied. β-Hydroxybutyrate (β-HB), a principal ketone body, exerts antiseizure effects, yet its downstream ionic mechanisms remain unclear. METHODS: We used 69 C57BL/6 mice, including males and females (4-week-old for ex vivo electrophysiology and calcium imaging and 8-week-old for in vivo seizure experiments). β-HB or saline was administered after the onset of status epilepticus, induced in mice by continuous hippocampal stimulation. Intrinsic excitability and excitatory synaptic currents on hippocampal granule cells were measured using the patch clamp technique. Calcium imaging was performed after viral delivery of a genetically encoded calcium indicator into the hippocampus. RESULTS: In vivo, β-HB rapidly reduced the duration of status epilepticus. At the cellular level, patch-clamp recordings showed that β-HB hyperpolarized dentate granule cells (DGCs) increased action potential threshold and reduced firing frequency. Moreover, β-HB suppressed excitatory synaptic transmission onto DGCs. At the network-level, β-HB perfusion significantly decreased DGC population activity by reducing neuronal excitability and excitatory synaptic currents. Mechanistically, pharmacological blockade of G protein-gated inwardly rectifying potassium (GIRK) channels prevents the β-HB-induced suppression of DGC intrinsic excitability, excitatory synaptic transmission, and population-level activity. In contrast, inhibition of adenosine triphosphate-sensitive potassium channels had no detectable impact on β-HB-mediated modulation of DGC intrinsic excitability or network responses. SIGNIFICANCE: These findings identify GIRK channels as a key downstream effector of β-HB signaling, providing a mechanistic link between ketogenic states and neuronal excitability, revealing a new mechanistic target for ketogenic therapies.

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