STRADA deficiency impairs cortical interneuron development in humans and mice.

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy syndrome (PMSE) is a rare neurodevelopmental disorder linked to STRADA gene deletions.
• The disorder is characterized by megalencephaly, drug-resistant epilepsy, and high mortality, often due to status epilepticus.
• GABAergic inhibitory interneurons (INs) are crucial for brain network balance, and their deficits are implicated in epilepsy.

Purpose of the Study:

• To investigate the role of inhibitory interneurons (INs) in the pathogenesis of PMSE.
• To analyze IN deficits in a mouse model with a 5-exon deletion in the Strada gene, mirroring human PMSE.
• To explore potential therapeutic targets for seizure prevention in PMSE.

Main Methods:

• Utilized a multimodal approach in a Strada-/- mouse model.
• Conducted RNA sequencing on wildtype and Strada-/- mouse cortex and striatum.
• Performed functional validation, including S6 phosphorylation analysis, on mouse and human brain tissue.

Main Results:

• Demonstrated a reduction of INs in the somatosensory cortex and an increase in the striatum of Strada-/- mice and human PMSE brain.
• RNA sequencing revealed altered gene expression related to INs, cytoskeletal function, and the mTOR pathway in Strada-/- mice.
• Confirmed enlarged INs and enhanced S6 phosphorylation in Strada-/- brain tissue.

Conclusions:

• STRADA/Strada loss causes failed IN migration, a novel finding in developmental, mTOR-associated megalencephaly syndromes.
• This interneuron migration impairment is a key feature of PMSE pathogenesis, potentially leading to reduced inhibitory modulation.
• Targeting INs presents a promising therapeutic strategy for seizure prevention in PMSE.