doi.org\/10.1002\/ana.78098<\/span><\/a><\/p>\nAbstract
\nObjective: The ketogenic diet, a high-fat, low-carbohydrate regimen, is
\noften used to treat drug-resistant seizures and is being studied for
\nAlzheimer’s disease and other neuropsychiatric disorders. However, its
\nmechanism of action remains unclear. \u03b2-hydroxybutyrate, a primary
\ncirculating ketone body produced by the ketogenic diet, may mediate its
\neffects on seizures by binding to a recently identified Gi-coupled
\nreceptor: hydrocarboxylic acid receptor 2 (HCAR2).<\/p>\n
Methods: RNAscope in situ hybridization assay and real-time quantitative
\npolymerase chain reaction were used to assess HCAR2 expression in the
\nmouse brain. We generated HCAR2-\/- using the CRISPR-Cas technique on an
\nS129 mouse background. Whole-cell current-clamp was performed to measure
\nthe passive and active membrane properties of hippocampal dentate
\ngranule cells. The voltage-clamp was performed to record synaptic
\ncurrents. Two complementary in vivo mouse models-continuous hippocampal
\nstimulation to induce status epilepticus (SE) and kindling-were used to
\ninduce seizures.<\/p>\n
Results: HCAR2 was localized in dentate granule cells and microglia. In
\nmice with HCAR2, \u03b2-hydroxybutyrate reduced neuronal excitability by
\nhyperpolarizing the resting membrane potential, raising the action
\npotential threshold, and reducing the firing frequency of dentate
\ngranule cells. \u03b2-hydroxybutyrate suppressed excitatory synaptic
\ntransmission. These effects were nullified in HCAR2-\/- mice. HCAR2-\/-
\nmice showed no cognitive impairment. Moreover, \u03b2-hydroxybutyrate did not
\naffect seizures in HCAR2-\/- mice. However, it diminished both the
\nduration and severity of seizures in HCAR2+\/+ mice.<\/p>\n
Interpretation: These findings demonstrate that HCAR2 mediates
\n\u03b2-hydroxybutyrate’s antiseizure effects by regulating neuronal
\nexcitability and synaptic transmission. These studies propose a new
\nmechanism for the antiseizure action of the ketogenic diet.<\/p>\n
\u4f55\u5352\u3088\u308d\u3057\u304f\u304a\u9858\u3044\u3044\u305f\u3057\u307e\u3059\u3002
\n\u85ac\u7406\u5b66\u8b1b\u5ea7\u3000\u5ddd\u6751\u5c06\u4ec1<\/p>\n","protected":false},"excerpt":{"rendered":"
4\u670822\u65e5\u62c5\u5f53\u306e\u85ac\u7406\u5b66\u8b1b\u5ea7\u306e\u5ddd\u6751\u3067\u3059\u3002 \u4ee5\u4e0b\u306e\u8ad6\u6587\u3092\u7d39\u4ecb\u3044\u305f\u3057\u307e\u3059\u3002 Hydroxycarboxylic Acid Receptor 2 Mediates \u03b2-hydroxybutyrate’s Antise…<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[3],"tags":[],"class_list":["post-582","post","type-post","status-publish","format-standard","hentry","category-journal-club"],"jetpack_sharing_enabled":true,"jetpack_featured_media_url":"","_links":{"self":[{"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=\/wp\/v2\/posts\/582","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=582"}],"version-history":[{"count":2,"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=\/wp\/v2\/posts\/582\/revisions"}],"predecessor-version":[{"id":585,"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=\/wp\/v2\/posts\/582\/revisions\/585"}],"wp:attachment":[{"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=582"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=582"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/neuroclub.jikei-neuroscience.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=582"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}