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To determine whether mice without \u03b12\u03b4-2 demonstrate hippocampal activation or histopathological changes associated with seizure activity, we measured expression of the activity-dependent gene c<jats:italic>-fos<\/jats:italic>and various histopathological correlates of temporal lobe epilepsy (TLE) in hippocampal tissue from wild-type (WT) and \u03b12\u03b4-2 knock-out (<jats:italic>CACNA2D2<\/jats:italic>KO) mice using immunohistochemical staining and confocal microscopy. Both genotypes demonstrated similarly sparse c-<jats:italic>fos<\/jats:italic>and<jats:italic>\u0394FosB<\/jats:italic>expressions within the hippocampal dentate granule cell layer (GCL) at baseline, consistent with no difference in basal activity of granule cells between genotypes. Surprisingly, when mice were assayed 1\u2005h after handling-associated convulsions, KO mice had fewer c-<jats:italic>fos<\/jats:italic>-positive cells but dramatically increased<jats:italic>\u0394FosB<\/jats:italic>expression in the dentate gyrus compared with WT mice. After administration of a subthreshold pentylenetetrazol dose, however, KO mice dentate had significantly more c-<jats:italic>fos<\/jats:italic>expression compared with WT mice. Other histopathological markers of TLE in these mice, including markers of neurogenesis, glial activation, and mossy fiber sprouting, were similar between WT and KO mice, apart from a small but statistically significant increase in hilar mossy cell density, opposite to what is typically found in mice with TLE. This suggests that the differences in seizure-associated dentate gyrus function in the absence of \u03b12\u03b4-2 protein are likely due to altered functional properties of the network without associated structural changes in the hippocampus at the typical age of seizure onset.<\/jats:p>","DOI":"10.1523\/eneuro.0486-23.2024","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T17:50:12Z","timestamp":1715795412000},"page":"ENEURO.0486-23.2024","source":"Crossref","is-referenced-by-count":4,"title":["Altered Hippocampal Activation in Seizure-Prone<i>CACNA2D2<\/i>Knock-out Mice"],"prefix":"10.1523","volume":"11","author":[{"given":"Alyssa B.","family":"Danis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9918-5174","authenticated-orcid":false,"given":"Ashlynn A.","family":"Gallagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1769-3792","authenticated-orcid":false,"given":"Ashley N.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9706-7871","authenticated-orcid":false,"given":"Arielle","family":"Isakharov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4392-3265","authenticated-orcid":false,"given":"Kathleen A.","family":"Beeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5623-5015","authenticated-orcid":false,"given":"Eric","family":"Schnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-16-06095.2001"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.2","doi-asserted-by":"publisher","DOI":"10.1002\/syn.890140102"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1514-19.2020"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.4","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1113\/JP282438","article-title":"Alpha2delta-2 is required for depolarization-induced suppression of excitation in Purkinje cells","volume":"600","author":"Beeson","year":"2022","journal-title":"J Physiol"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.5","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1063(1997)7:3<307::AID-HIPO6>3.0.CO;2-H"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2005.00311.x"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.7","doi-asserted-by":"publisher","DOI":"10.1016\/S1044-7431(03)00207-0"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M308778200"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.9","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0429-22.2022"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan4074"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.11","doi-asserted-by":"publisher","DOI":"10.1002\/cne.902960402"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1008-21.2022"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.13","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a003947"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.14","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.11-09-02795.1991"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.15","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7606"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.020"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.17","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20693"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.05.023"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.19","doi-asserted-by":"crossref","first-page":"406","DOI":"10.3109\/07853899908998798","article-title":"Neurological channelopathies: diagnosis and therapy in the new millennium","volume":"31","author":"Davies","year":"1999","journal-title":"Ann Med"},{"key":"2024051510500696000_11.5.ENEURO.0486-23.2024.20","unstructured":"de Lanerolle NC , Lee TS , Spencer DD (2012) Histopathology of human epilepsy. 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