STRADA deficiency impairs cortical interneuron development in humans and mice

Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy syndrome (PMSE/STRADA-related disease) is a rare neurodevelopmental disorder characterized by megalencephaly, early-onset drug-resistant epilepsy, neurocognitive impairment, and high early mortality, often due to status epilepticus. PMSE is caused by a multiexon deletion in the STRADA/LYK5 gene, encoding STRADA protein, which regulates the mechanistic target of rapamycin (mTOR) pathway. GABAergic inhibitory interneurons (INs) critically modulate excitatory:inhibitory balance in cortical networks, and IN deficits contribute to epileptogenesis in several epileptic encephalopathies. However, no studies to date have investigated INs in PMSE. We demonstrate that Strada/STRADA loss causes a reduction of multiple IN subtypes in the cerebral cortex and a corresponding increase in the striatum, representative of the remnant ganglionic eminence progenitor origin, in both Strada-/- mice and in a case of human PMSE brain tissue, suggestive of an IN migration defect. RNA sequencing comparing wildtype control to Strada-/- mouse cortex and striatum corroborates these findings, revealing increased IN-related gene expression (e.g., Dlx2) in the striatum. mTOR-associated genes (Lamp5, Cryab) are differentially expressed in the developing cortex, and cytoskeletal-associated genes (e.g., Tppp3, Kank4, Map1a) are differentially expressed in the developing cortex and mature striatum of Strada-/- mice. Functional validation confirms enlarged INs in Strada/STRADA-deficient brain, associated with mTOR hyperactivation. Together, these results suggest that STRADA/Strada loss may contribute to failed IN migration, the first such report in a developmental mTORassociated megalencephaly syndrome, highlighting INs as a therapeutic target for seizure prevention in PMSE.