STRADA deficiency impairs cortical interneuron development in humans and mice

28/10/2026

AI Summary

STRADA loss reduces multiple cortical GABAergic interneuron subtypes and increases striatal interneuron remnants, indicating defective migration in mice and human PMSE tissue.
Transcriptomics reveal elevated interneuron-related gene expression in striatum and differential expression of mTOR and cytoskeletal genes in developing cortex and mature striatum.
Functional studies show enlarged interneurons with mTOR hyperactivation, implicating failed interneuron migration and interneurons as therapeutic targets to prevent seizures in PMSE.

TL;DR (AI Generated)

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.

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.

Basic summary

Neurobiol Dis. 2026 Oct 27:107665. doi: 10.1016/j.nbd.2026.107665. Online ahead of print.

ABSTRACT

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.

PMID:42946146 | DOI:10.1016/j.nbd.2026.107665

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