β-Hydroxybutyrate reduces neuronal excitability via GIRK channels
Soudabeh Naderi1, John Williamson1, Jhanvi Patel1
1Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.
Epilepsia
|August 10, 2026
Summary
The ketogenic diet
Area of Science:
- Neuroscience
- Biochemistry
- Epilepsy Research
Background:
- The ketogenic diet is a recognized treatment for drug-resistant epilepsy.
- The precise molecular mechanisms linking metabolic changes to seizure control are not fully understood.
- Beta-hydroxybutyrate (β-HB), a key ketone body, shows antiseizure properties, but its ionic targets are unclear.
Purpose of the Study:
- To investigate the downstream ionic mechanisms through which β-hydroxybutyrate (β-HB) exerts its antiseizure effects.
- To elucidate the cellular and network-level actions of β-HB in the hippocampus.
- To identify specific ion channels involved in β-HB's modulation of neuronal excitability.
Main Methods:
- Utilized C57BL/6 mice for in vivo and ex vivo experiments.
- Induced status epilepticus via hippocampal stimulation, followed by β-HB or saline administration.
- Employed patch-clamp electrophysiology to assess neuronal excitability and synaptic currents in dentate granule cells (DGCs).
- Conducted calcium imaging to evaluate network activity.
- Investigated the role of G protein-gated inwardly rectifying potassium (GIRK) channels and ATP-sensitive potassium channels.
Main Results:
- β-HB administration significantly reduced seizure duration in vivo.
- At the cellular level, β-HB hyperpolarized DGCs, raised action potential thresholds, and decreased firing rates.
- β-HB suppressed excitatory synaptic transmission and overall DGC population activity.
- Pharmacological blockade of GIRK channels abolished the effects of β-HB on neuronal excitability and network activity.
- Inhibition of ATP-sensitive potassium channels did not affect β-HB's actions.
Conclusions:
- GIRK channels are identified as critical downstream mediators of β-HB signaling.
- This study establishes a mechanistic link between ketogenic metabolism and reduced neuronal excitability.
- GIRK channels represent a potential therapeutic target for enhancing ketogenic therapies in epilepsy.
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