{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:07:42Z","timestamp":1790662062943,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,1,5]],"date-time":"2021-01-05T00:00:00Z","timestamp":1609804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002367","name":"Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["QYZDJ\u2010SSW\u2010SMC010"],"award-info":[{"award-number":["QYZDJ\u2010SSW\u2010SMC010"]}],"id":[{"id":"10.13039\/501100002367","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["18JC1410100"],"award-info":[{"award-number":["18JC1410100"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Mutations of the cyclin\u2010dependent kinase\u2010like 5 (<jats:italic>CDKL5<\/jats:italic>) gene cause severe neurodevelopmental disorders characterized by intractable epilepsy, intellectual disability, and autism. Multiple mouse models generated for mechanistic studies have exhibited phenotypes similar to some human pathological features, but none of the models has developed one of the major symptoms affecting CDKL5 deficiency disorder (CDD) patients: intractable recurrent seizures. As disrupted neuronal excitation\/inhibition balance is closely associated with the activity of glutamatergic and \u03b3\u2010aminobutyric acidergic (GABAergic) neurons, our aim was to study the effect of the loss of CDKL5 in different types of neurons on epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using the Cre\u2010LoxP system, we generated conditional knockout (cKO) mouse lines allowing CDKL5 deficiency in glutamatergic or GABAergic neurons. We employed noninvasive video recording and in vivo electrophysiological approaches to study seizure activity in these <jats:italic>Cdkl5<\/jats:italic> cKO mice. Furthermore, we conducted Timm staining to confirm a morphological alteration, mossy fiber sprouting, which occurs with limbic epilepsy in both human and mouse brains. Finally, we performed whole\u2010cell patch clamp in dentate granule cells to investigate cell\u2010intrinsic properties and synaptic excitatory activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate that Emx1\u2010 or CamK2\u03b1\u2010derived <jats:italic>Cdkl5<\/jats:italic> cKO mice manifest high\u2010frequency spontaneous seizure activities recapitulating the epilepsy of CDD patients, which ultimately led to sudden death in mice. However, <jats:italic>Cdkl5<\/jats:italic> deficiency in GABAergic neurons does not generate such seizures. The seizures were accompanied by typical epileptic features including higher amplitude spikes for epileptiform discharges and abnormal hippocampal mossy fiber sprouting. We also found an increase in spontaneous and miniature excitatory postsynaptic current frequencies but no change in amplitudes in the dentate granule cells of Emx1\u2010cKO mice, indicating enhanced excitatory synaptic activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our study demonstrates that <jats:italic>Cdkl5<\/jats:italic> cKO mice, serving as an animal model to study recurrent spontaneous seizures, have potential value for the pathological study of CDD\u2010related seizures and for therapeutic innovation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.16805","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T06:38:16Z","timestamp":1609915096000},"page":"517-528","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures"],"prefix":"10.1111","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6686-9097","authenticated-orcid":false,"given":"Hong\u2010Tao","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Neuroscience State Key Laboratory of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai China"},{"name":"School of Life Science and Technology Xinxiang Medical University Xinxiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Ai","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience State Key Laboratory of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience State Key Laboratory of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen\u2010Sen","family":"Lou","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience State Key Laboratory of Neuroscience Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Sciences Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience State Key Laboratory of Neuroscience Center for Excellence in Brain 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