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Furthermore, they show increased excitability in vitro in hippocampal slices obtained from human MTLE specimens or animal epilepsy models. Although these changes promote CA2 to contribute to epileptic activity (EA) in vivo, the role of CA2 in the epileptic network within and beyond the sclerotic hippocampus is still unclear. We used the intrahippocampal kainate mouse model for MTLE, which recapitulates most features of the human disease including pharmacoresistant epileptic seizures and hippocampal sclerosis, with preservation of dentate gyrus (DG) granule cells and CA2 pyramidal cells. In vivo recordings with electrodes in CA2 and the DG showed that EA occurs at high coincidence between the ipsilateral DG and CA2 and current source density analysis of silicon probe recordings in dorsal ipsilateral CA2 revealed CA2 as a local source of EA. Cell\u2010specific viral tracing in Amigo2\u2010icreERT2 mice confirmed the preservation of the axonal projection from ipsilateral CA2 pyramidal cells to contralateral CA2 under epileptic conditions and indeed, EA propagated from ipsi\u2010 to contralateral CA2 with increasing likelihood with time after KA injection, but always at lower intensity than within the ipsilateral hippocampus. Furthermore, we show that CA2 presents with local theta oscillations and like the DG, shows a pathological reduction of theta frequency already from 2\u2009days after KA onward. The early changes in activity might be facilitated by the loss of glutamic acid decarboxylase 67 (<jats:italic>Gad67<\/jats:italic>) mRNA\u2010expressing interneurons directly after the initial <jats:italic>status epilepticus<\/jats:italic> in ipsi\u2010 but not contralateral CA2. Together, our data highlight CA2 as an active player in the epileptic network and with its contralateral connections as one possible router of aberrant activity.<\/jats:p>","DOI":"10.1002\/hipo.23479","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T20:37:52Z","timestamp":1669322272000},"page":"223-240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Integration of the <scp>CA2<\/scp> region in the hippocampal network during epileptogenesis"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6691-7194","authenticated-orcid":false,"given":"Antje","family":"Kilias","sequence":"first","affiliation":[{"name":"Institute for Physiology I, Medical Faculty University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Tulke","sequence":"additional","affiliation":[{"name":"Experimental Epilepsy Research, Department of Neurosurgery Medical Center \u2010 University of Freiburg, Faculty of Medicine  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-5519","authenticated-orcid":false,"given":"Nicole","family":"Barheier","sequence":"additional","affiliation":[{"name":"Experimental Epilepsy Research, Department of Neurosurgery Medical Center \u2010 University of Freiburg, Faculty of Medicine  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7358-003X","authenticated-orcid":false,"given":"Patrick","family":"Ruther","sequence":"additional","affiliation":[{"name":"Microsystem Materials Laboratory, Department of Microsystems Engineering (IMTEK) University of Freiburg  Freiburg Germany"},{"name":"Center BrainLinks\u2010BrainTools University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5601-9833","authenticated-orcid":false,"given":"Ute","family":"H\u00e4ussler","sequence":"additional","affiliation":[{"name":"Experimental Epilepsy Research, Department of Neurosurgery Medical Center \u2010 University of Freiburg, Faculty of Medicine  Freiburg Germany"},{"name":"Center BrainLinks\u2010BrainTools University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,24]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38052"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.11.024"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/hipo.20011"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(00)01682-9"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12220"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2016.04.024"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2014.00104"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(98)00401-1"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137221"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0245-16.2016"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4699-08.2009"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.04.013"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23263"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2001.10401.x"},{"key":"e_1_2_7_16_1","volume-title":"The mouse brain in stereotaxic coordinates","author":"Franklin K. 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