{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T23:55:34Z","timestamp":1792108534111,"version":"4.4.0"},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2014,12,19]],"date-time":"2014-12-19T00:00:00Z","timestamp":1418947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006510","name":"Duke","doi-asserted-by":"crossref","award":["4410161"],"award-info":[{"award-number":["4410161"]}],"id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006510","name":"Duke","doi-asserted-by":"crossref","award":["3912247"],"award-info":[{"award-number":["3912247"]}],"id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Duke Translational Research Institute","award":["SOMVP-2012"],"award-info":[{"award-number":["SOMVP-2012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2015,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Mutations in the <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>1\u03b13 subunit of the neuronal Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase are thought to be responsible for seizures, hemiplegias, and other symptoms of alternating hemiplegia of childhood (<jats:styled-content style=\"fixed-case\">AHC<\/jats:styled-content>). However, the mechanisms through which <jats:italic><jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>1A3<\/jats:italic> mutations mediate their pathophysiologic consequences are not yet understood. The following hypotheses were investigated: (1) Our novel knock\u2010in mouse carrying the most common heterozygous mutation causing <jats:styled-content style=\"fixed-case\">AHC<\/jats:styled-content> (D801N) will exhibit the manifestations of the human condition and display predisposition to seizures; and (2) the underlying pathophysiology in this mouse model involves increased excitability in response to electrical stimulation of Schaffer collaterals and abnormal predisposition to spreading depression (<jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated the D801N mutant mouse (Mashlool, Mashl<jats:sup>+\/\u2212<\/jats:sup>) and compared mutant and wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) littermates. Behavioral tests, amygdala kindling, flurothyl\u2010induced seizure threshold, spontaneous recurrent seizures (<jats:styled-content style=\"fixed-case\">SRS<\/jats:styled-content>), and other paroxysmal activities were compared between groups. In vitro electrophysiologic slice experiments on hippocampus were performed to assess predisposition to hyperexcitability and <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mutant mice manifested a distinctive phenotype similar to that of humans with <jats:styled-content style=\"fixed-case\">AHC<\/jats:styled-content>. They had abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, and <jats:styled-content style=\"fixed-case\">SRS<\/jats:styled-content>, as well as predisposition to kindling, to flurothyl\u2010induced seizures, and to sudden unexpected death. Hippocampal slices of mutants, in contrast to <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> animals, showed hyperexcitable responses to 1\u00a0Hz pulse\u2010trains of electrical stimuli delivered to the Schaffer collaterals and had significantly longer duration of K<jats:sup>+<\/jats:sup>\u2010induced <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content> responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our model reproduces the major characteristics of human <jats:styled-content style=\"fixed-case\">AHC<\/jats:styled-content>, and indicates that <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>1\u03b13 dysfunction results in abnormal short\u2010term plasticity with increased excitability (potential mechanism for seizures) and a predisposition to more severe <jats:styled-content style=\"fixed-case\">SD<\/jats:styled-content> responses (potential mechanism for hemiplegias). This model of the human condition should help in understanding the molecular pathways underlying these phenotypes and may lead to identification of novel therapeutic strategies of <jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>1\u03b13 related disorders and seizures.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.12878","type":"journal-article","created":{"date-parts":[[2014,12,19]],"date-time":"2014-12-19T12:05:41Z","timestamp":1418990741000},"page":"82-93","source":"Crossref","is-referenced-by-count":87,"title":["Knock\u2010in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization"],"prefix":"10.1111","volume":"56","author":[{"given":"Arsen S.","family":"Hunanyan","sequence":"first","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina A.","family":"Fainberg","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Linabarger","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Arehart","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Soren","family":"Leonard","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed M.","family":"Adil","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley R.","family":"Helseth","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology Department of Pediatrics School of Medicine Duke University Durham North Carolina U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda K.","family":"Swearingen","sequence":"additional","affiliation":[{"name":"Neurotransgenic Laboratory Department of Neurobiology School of Medicine Duke University Durham North Carolina 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