{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:44:06Z","timestamp":1776699846511,"version":"3.51.2"},"reference-count":44,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,6,11]],"date-time":"2018-06-11T00:00:00Z","timestamp":1528675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005572","name":"Duke Institute for Brain Sciences, Duke University","doi-asserted-by":"publisher","award":["4510874"],"award-info":[{"award-number":["4510874"]}],"id":[{"id":"10.13039\/100005572","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006510","name":"Duke University","doi-asserted-by":"publisher","award":["3912247"],"award-info":[{"award-number":["3912247"]}],"id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006510","name":"Duke University","doi-asserted-by":"publisher","award":["4410161"],"award-info":[{"award-number":["4410161"]}],"id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase dysfunction, primary (mutation) or secondary (energy crisis, neurodegenerative disease) increases neuronal excitability in the brain. To evaluate the mechanisms underlying such increased excitability we studied mice carrying the <jats:italic>D801N<\/jats:italic> mutation, the most common mutation causing human disease, specifically alternating hemiplegia of childhood (<jats:styled-content style=\"fixed-case\">AHC<\/jats:styled-content>) including epilepsy. Because the gene is expressed in all neurons, particularly <jats:styled-content style=\"fixed-case\">\u03b3\u2010aminobutyric acid (GABA)<\/jats:styled-content>ergic interneurons, we hypothesized that the pathophysiology would involve both pyramidal cells and interneurons and that fast\u2010spiking interneurons, which have increased firing rates, would be most vulnerable.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed extracellular recordings, as well as whole\u2010cell patch clamp recordings from pyramidal cells and interneurons, in the <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 region on hippocampal slices. We also performed immunohistochemistry from hippocampal sections to count <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 pyramidal cells as well as parvalbumin\u2010positive interneurons. In addition, we performed video\u2014electroencephalography (EEG) recordings from the dorsal hippocampal <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 region.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that juvenile knock\u2010in mice carrying the above mutation reproduce the human phenotype of <jats:styled-content style=\"fixed-case\">AHC<\/jats:styled-content>. We then demonstrated in the <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 region of these mice the following findings as compared to wild type: (1) Increased number of spikes evoked by electrical stimulation of Schaffer collaterals; (2) equalization by bicuculline of the number of spikes induced by Schaffer collateral stimulation; (3) reduced miniature, spontaneous, and evoked inhibitory postsynaptic currents, but no change in excitatory postsynaptic currents; (4) robust action potential frequency adaptation in response to depolarizing current injection in <jats:styled-content style=\"fixed-case\">CA<\/jats:styled-content>1 fast\u2010spiking interneurons; and (5) no change in the number of pyramidal cells, but reduced number of parvalbumin positive interneurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our data indicate that, in our genetic model of Atp1\u03b13 mutation, there is increased excitability and marked dysfunction in <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic inhibition. This supports the performance of further investigations to determine if selective expression of the mutation in <jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>ergic and or glutamatergic neurons is necessary and sufficient to result in the behavioral phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.14441","type":"journal-article","created":{"date-parts":[[2018,6,11]],"date-time":"2018-06-11T14:56:19Z","timestamp":1528728979000},"page":"1455-1468","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Mechanisms of increased hippocampal excitability in the <i>Mashl<\/i><sup><i>+\/\u2212<\/i><\/sup> mouse model of Na<sup>+<\/sup>\/K<sup>+<\/sup>\u2010<scp>ATP<\/scp>ase dysfunction"],"prefix":"10.1111","volume":"59","author":[{"given":"Arsen S.","family":"Hunanyan","sequence":"first","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley R.","family":"Helseth","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elie","family":"Abdelnour","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bassil","family":"Kherallah","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monisha","family":"Sachdev","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leeyup","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Duke University School of Medicine Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"Masoud","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan","family":"Richardson","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Medical Center Durham NC USA"},{"name":"Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham NC USA"},{"name":"Veterans Affairs Mid\u2010Atlantic Region Mental Illness Research, Education, and Clinical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Victor","family":"Nadler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cancer Biology Duke University Medical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott D.","family":"Moore","sequence":"additional","affiliation":[{"name":"Durham Veterans Affairs Medical Center Durham NC USA"},{"name":"Department of Psychiatry and Behavioral Sciences Duke University Medical Center Durham NC USA"},{"name":"Veterans Affairs Mid\u2010Atlantic Region Mental Illness Research, Education, and Clinical Center Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0363-8715","authenticated-orcid":false,"given":"Mohamad A.","family":"Mikati","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics Duke University Medical Center Durham NC USA"},{"name":"Department of Neurobiology Duke University School of Medicine Durham NC 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