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However, its mechanism of action remains unclear. \u03b2\u2010hydroxybutyrate, a primary circulating ketone body produced by the ketogenic diet, may mediate its effects on seizures by binding to a recently identified Gi\u2010coupled receptor: hydrocarboxylic acid receptor 2 (HCAR2).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      RNAscope in situ hybridization assay and real\u2010time quantitative polymerase chain reaction were used to assess HCAR2 expression in the mouse brain. We generated HCAR2\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/\n                      <jats:sup>\u2212<\/jats:sup>\n                      using the CRISPR\u2010Cas technique on an S129 mouse background. Whole\u2010cell current\u2010clamp was performed to measure the passive and active membrane properties of hippocampal dentate granule cells. The voltage\u2010clamp was performed to record synaptic currents. Two complementary in vivo mouse models\u2014continuous hippocampal stimulation to induce status epilepticus (SE) and kindling\u2014were used to induce seizures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HCAR2 was localized in dentate granule cells and microglia. In mice with HCAR2, \u03b2\u2010hydroxybutyrate reduced neuronal excitability by hyperpolarizing the resting membrane potential, raising the action potential threshold, and reducing the firing frequency of dentate granule cells. \u03b2\u2010hydroxybutyrate suppressed excitatory synaptic transmission. These effects were nullified in HCAR2\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/\n                      <jats:sup>\u2212<\/jats:sup>\n                      mice. HCAR2\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/\n                      <jats:sup>\u2212<\/jats:sup>\n                      mice showed no cognitive impairment. Moreover, \u03b2\u2010hydroxybutyrate did not affect seizures in HCAR2\n                      <jats:sup>\u2212<\/jats:sup>\n                      \/\n                      <jats:sup>\u2212<\/jats:sup>\n                      mice. However, it diminished both the duration and severity of seizures in HCAR2\n                      <jats:sup>+<\/jats:sup>\n                      \/\n                      <jats:sup>+<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>These findings demonstrate that HCAR2 mediates \u03b2\u2010hydroxybutyrate's antiseizure effects by regulating neuronal excitability and synaptic transmission. These studies propose a new mechanism for the antiseizure action of the ketogenic diet. ANN NEUROL 2026;99:809\u2013824<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78098","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:13:09Z","timestamp":1764223989000},"page":"809-824","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Hydroxycarboxylic Acid Receptor 2 Mediates \u03b2\u2010hydroxybutyrate's Antiseizure Effect in Mice"],"prefix":"10.1002","volume":"99","author":[{"given":"Soudabeh","family":"Naderi","sequence":"first","affiliation":[{"name":"Department of Neurology University of Virginia  Charlottesville VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Williamson","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Virginia  Charlottesville VA 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