Kv7.2 loss-of-function causes early hyperexcitability and network remodelling

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Loss-of-function (LOF) variants in KCNQ2, encoding the Kv7.2 potassium channel subunit, are associated with a spectrum of neonatal epilepsies, from self-limiting familial neonatal epilepsy (SeLFNE) to developmental and epileptic encephalopathy (DEE).
• Understanding the precise developmental impact of these variants is crucial for elucidating disease mechanisms and identifying therapeutic targets.

Purpose of the Study:

• To investigate the longitudinal and multimodal consequences of KCNQ2 LOF variants on human neuronal development.
• To characterize the functional, transcriptomic, and structural changes occurring at single-cell and network levels in patient-derived neuronal models.

Main Methods:

• Generation of human neuronal models from patients with KCNQ2-DEE and KCNQ2-SeLFNE.
• Longitudinal, multimodal analysis including electrophysiology, transcriptomics, and structural imaging.
• Assessment of M-current density, intrinsic excitability, network activity, synaptic gene expression, and axon initial segment (AIS) morphology.

Main Results:

• KCNQ2 LOF variants induced a biphasic neuronal dysfunction: early hyperexcitability with reduced M-current (rescued by Retigabine), followed by normalized excitability but maladaptive network remodeling.
• Transcriptomic analysis revealed dynamic changes in synaptic gene expression, with initial upregulation then downregulation.
• Structural analysis showed impaired presynaptic density and AIS maturation, with reduced AIS plasticity.

Conclusions:

• KCNQ2 LOF variants disrupt human neuronal maturation through dynamic, biphasic alterations in function, gene expression, and structure.
• These findings provide critical insights into the complex pathogenesis of KCNQ2-related epilepsies and suggest potential therapeutic avenues.