STRADA deficiency impairs cortical interneuron development in humans and mice

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 STRADA , 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 Strada ^-/- mouse model engineered with the same causative 5-exon deletion identified in human PMSE. We demonstrate that Strada / STRADA 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 Strada -/- mice and a single PMSE brain tissue specimen. RNA sequencing comparing wildtype to Strada -/- cortex and striatum corroborated these findings, revealing increased IN-related gene expression (e.g., Dlx2 ) in the striatum and decreased IN-related gene expression (e.g., Pvalb ) in the developing cortex. Cytoskeletal (e.g., Tpp3 , Kank4 , Map1a ) and mTOR-associated genes (e.g., Rictor , Cryab ) are differentially expressed in the developing cortex, mature striatum, and mature cortex of Strada ^-/- mice. Functional validation confirmed enlarged INs in mouse and human Strada / STRADA -deficient brain and enhanced S6 phosphorylation in Strada ^-/- striatum. Together, these findings suggest STRADA / Strada loss contributes to failed IN migration — the first such report in a developmental, mTOR-associated megalencephaly syndrome — highlighting INs as a therapeutic target for seizure prevention in PMSE.