{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:55:39Z","timestamp":1792788939123,"version":"4.5.0"},"reference-count":39,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Temporal lobe epilepsy (TLE) is characterized by synaptic dysfunction for which targeted therapies are lacking. Hydroxysteroid dehydrogenase\u2010like 2 (HSDL2) was previously identified as a potential regulator in TLE, but its precise functional and mechanistic role remained unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We compared HSDL2 protein expression in cortical tissues from patients with drug\u2010resistant TLE and a kainic acid (KA)\u2010induced mouse model via western blotting. Cellular localization was determined by immunofluorescence co\u2010staining with neuronal (NeuN and PSD95), astrocytic (GFAP), and microglial (IBA1) markers. Adeno\u2010associated virus (AAV) vectors were used to overexpress or knock down HSDL2 in the mouse hippocampus, followed by behavioral seizure assessments using pentylenetetrazol (PTZ) and chronic monitoring of spontaneous recurrent seizures (SRS). Underlying mechanisms were investigated through protein\u2013protein interaction, patch\u2010clamp electrophysiology, and quantitative co\u2010immunoprecipitation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HSDL2 was significantly upregulated in both human TLE foci and the KA\u2010induced epileptic mouse brain. It was localized to both neurons and astrocytes. In\u00a0vivo, HSDL2 overexpression prolonged the latency to PTZ\u2010induced seizures and reduced SRS frequency, whereas its knockdown exacerbated seizure severity and duration. Mechanistically, HSDL2 enhanced the membrane localization of postsynaptic density protein 95 (PSD95) and promoted its phosphorylation. This modification disrupted the physical interaction between PSD95 and the N\u2010methyl\u2010D\u2010aspartate receptor (NMDAR) NR2B and NR2A subunits, leading to a reduction in NMDAR\u2010mediated synaptic currents and neuronal hyperexcitability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings identify HSDL2 as a novel endogenous antiseizure protein that confers protection in epilepsy by modulating synaptic excitability. Specifically, HSDL2 regulates the PSD95\u2010NMDAR complex through post\u2010translational modification of PSD95, thereby inhibiting excessive NMDAR activity. Its therapeutic modulation may offer a strategy for drug development in TLE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70826","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T04:26:42Z","timestamp":1773116802000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>HSDL2<\/scp>\n                    Suppresses Epileptic Seizures Through Phosphorylation\u2010Dependent Modulation of the\n                    <scp>PSD95<\/scp>\n                    \u2010\n                    <scp>NMDAR<\/scp>\n                    Signaling Axis"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3180-5600","authenticated-orcid":false,"given":"Yan","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang","family":"Hui","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Demei","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Neurology The Second Affiliated Hospital of Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0606-561X","authenticated-orcid":false,"given":"Wang","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing Key Laboratory of Neurology  Chongqing China"},{"name":"Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32596-0"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.24"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2024.1384805"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.775781"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22083860"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000001010"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-023-01174-5"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.15540"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25189869"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10111702"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2025.107090"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2024.e00447"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8588-y"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2009.08.001"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk9681"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S205316"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000036"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12957-023-03176-6"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2025.156960"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/01616412.2025.2495933"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27204-9"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(02)00064-7"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1299"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-024-03944-9"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2016.02.011"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2153"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.04.024"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00734"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.31083\/JIN25710"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80921-6"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21062094"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2022.02.030"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pnpbp.2017.11.016"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-016-9745-1"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2024-09.2010"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2013.04.005"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080004"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.036"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600966200"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.70826","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cns.70826","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cns.70826","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T15:22:45Z","timestamp":1777562565000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cns.70826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/cns.70826"],"URL":"https:\/\/doi.org\/10.1002\/cns.70826","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-08-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-09","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70826"}}