{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T18:52:57Z","timestamp":1773168777195,"version":"3.50.1"},"reference-count":33,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T00:00:00Z","timestamp":1749772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>De novo somatic mutations in mTOR pathway genes during fetal development lead to focal malformation of cortical development (FMCD) and epilepsy. This FMCD is characterized by misplacement of enlarged pyramidal neurons displaying increased mTOR activity. Whether these neurons display enhanced excitability has remained an open question. Several lines of evidence in experimental murine FMCD suggest that FMCD neurons display a complex set of alterations, including dendrite hypertrophy associated with decreased rheobase but opposing changes in excitability due to the abnormal expression of hyperpolarization\u2010activated cyclic nucleotide\u2010gated isoform 4 (HCN4) channels. However, there is very little information on synaptic excitatory activity and how these different alterations are integrated to shape their firing rate, particularly at the onset of seizures at approximately postnatal day 21 (P21) and after the establishment of recurrent seizures (at P28).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address these questions, we generated FMCD by using in utero electroporation to express a constitutively active Rheb (Rheb<jats:sup>S16H<\/jats:sup>), an mTOR canonical activator, in layer 2\/3 cortical pyramidal neurons, and assessed its effects on pyramidal cell excitability at P21 and P28 using acute brain slices in\u00a0vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At both time points, Rheb<jats:sup>S16H<\/jats:sup> neurons exhibited cytomegaly along with increased dendritic complexity and abnormal HCN current expression. However, they displayed distinct changes in the properties of spines and excitatory postsynaptic currents (EPSCs). Specifically, there was an increase in EPSC amplitude at both ages, but whereas no change in frequency was observed at P21, a decrease in frequency was seen at P28. Experimental data\u2010driven multicompartment single\u2010cell computational models investigating dysmorphic neuronal excitability at P28 predicted that HCN4 channels, rather than excitatory synaptic inputs, predominantly contribute to the firing of Rheb<jats:sup>S16H<\/jats:sup> neurons.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Overall, these experimental and computational findings advance our understanding of the mechanisms of excitability of Rheb<jats:sup>S16H<\/jats:sup> neurons, with implications for FMCD\u2010related seizure activity due to mTOR hyperactivity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18456","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T11:03:31Z","timestamp":1749812611000},"page":"3555-3570","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Relative roles of <scp>HCN4<\/scp> and synaptic excitation in pyramidal neuron firing rates in a hyperactive Rheb\u2010<scp>mTOR<\/scp> condition"],"prefix":"10.1111","volume":"66","author":[{"given":"Alexandra Pierri","family":"Chatzikalymniou","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Stanford University  Stanford California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie A.","family":"Getz","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Cellular &amp; Molecular Physiology Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youfen","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Cellular &amp; Molecular Physiology Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhruv R.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Cellular &amp; Molecular Physiology Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Soltesz","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Stanford University  Stanford California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3496-3385","authenticated-orcid":false,"given":"Ang\u00e9lique","family":"Bordey","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Wu Tsai Institute, Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Cellular &amp; 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