{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:10:26Z","timestamp":1785409826757,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,1]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["K08NS140393"],"award-info":[{"award-number":["K08NS140393"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"name":"STMD-Maryland Technology Development Corporation","award":["2025-R2-MSCRFL-00012"],"award-info":[{"award-number":["2025-R2-MSCRFL-00012"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy syndrome (PMSE\/STRADA-related disorder) is a rare neurodevelopmental disorder characterized by megalencephaly (ME), early-onset drug-resistant epilepsy, neurocognitive impairment, and high early mortality, often due to status epilepticus. PMSE is caused by a multi-exon deletion in\n                  <jats:italic>STRADA<\/jats:italic>\n                  , encoding STRADA, which regulates the mechanistic target of rapamycin (mTOR) pathway. GABAergic inhibitory interneurons (INs) critically modulate the excitatory:inhibitory balance in cortical and hippocampal networks, and IN deficits contribute to epileptogenesis in several epileptic encephalopathies. However, no studies have investigated INs in PMSE. We used a multimodal approach to study INs in a\n                  <jats:italic>Strada<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  mouse model engineered with the same causative 5-exon deletion identified in human PMSE. We demonstrate that\n                  <jats:italic>Strada<\/jats:italic>\n                  \/\n                  <jats:italic>STRADA<\/jats:italic>\n                  loss causes a reduction of INs in the somatosensory cortex and a corresponding increase in the striatum, representative of remnant ganglionic eminence progenitor origin, in\n                  <jats:italic>Strada<\/jats:italic>\n                  -\/- mice and a single PMSE brain tissue specimen. RNA sequencing comparing wildtype to\n                  <jats:italic>Strada<\/jats:italic>\n                  -\/- cortex and striatum corroborated these findings, revealing increased IN-related gene expression (e.g.,\n                  <jats:italic>Dlx2<\/jats:italic>\n                  ) in the striatum and decreased IN-related gene expression (e.g.,\n                  <jats:italic>Pvalb<\/jats:italic>\n                  ) in the developing cortex. Cytoskeletal (e.g.,\n                  <jats:italic>Tpp3<\/jats:italic>\n                  ,\n                  <jats:italic>Kank4<\/jats:italic>\n                  ,\n                  <jats:italic>Map1a<\/jats:italic>\n                  ) and mTOR-associated genes (e.g.,\n                  <jats:italic>Rictor<\/jats:italic>\n                  ,\n                  <jats:italic>Cryab<\/jats:italic>\n                  ) are differentially expressed in the developing cortex, mature striatum, and mature cortex of\n                  <jats:italic>Strada<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  mice. Functional validation confirmed enlarged INs in mouse and human\n                  <jats:italic>Strada<\/jats:italic>\n                  \/\n                  <jats:italic>STRADA<\/jats:italic>\n                  -deficient brain and enhanced S6 phosphorylation in\n                  <jats:italic>Strada<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  striatum. Together, these findings suggest\n                  <jats:italic>STRADA<\/jats:italic>\n                  \/\n                  <jats:italic>Strada<\/jats:italic>\n                  loss contributes to failed IN migration \u2014 the first such report in a developmental, mTOR-associated megalencephaly syndrome \u2014 highlighting INs as a therapeutic target for seizure prevention in PMSE.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:label>-<\/jats:label>\n                      <jats:p>\n                        Reduced numbers of cortical inhibitory interneurons were observed in the cerebral cortex of\n                        <jats:italic>\n                          Strada\n                          <jats:sup>-\/-<\/jats:sup>\n                        <\/jats:italic>\n                        mice, with striatal interneuron aggregation\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>-<\/jats:label>\n                      <jats:p>\n                        Reduced numbers of cortical inhibitory interneurons, with an aggregation in striatum, were observed in human PMSE brain, supporting the observations in\n                        <jats:italic>\n                          Strada\n                          <jats:sup>-\/-<\/jats:sup>\n                        <\/jats:italic>\n                        mouse\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>-<\/jats:label>\n                      <jats:p>\n                        Transcriptomic analysis in\n                        <jats:italic>\n                          Strada\n                          <jats:sup>-\/-<\/jats:sup>\n                        <\/jats:italic>\n                        mice reveals evidence of early developmental interneuron and cytoskeletal dysfunction\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>-<\/jats:label>\n                      <jats:p>We introduce a loss of cortical interneurons as a salient feature of PMSE developmental pathogenesis, potentially contributing to a loss of inhibitory modulation<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:label>-<\/jats:label>\n                      <jats:p>This is the first study proposing interneuron migration impairment in the developmental pathogenesis of an mTOR-associated megalencephaly syndrome<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                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