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

Nina Dirkx1,2, Marcus Kaji1,3,4, Els De Vriendt3

  • 1Translational Epilepsy Genomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, 2610, Belgium.

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Summary
This summary is machine-generated.

Loss-of-function variants in KCNQ2 cause neonatal epilepsies. These KCNQ2 variants lead to biphasic neuronal dysfunction, impacting network activity and structure during development.

Keywords:
Kv7.2 channel dysfunctionM-currenthuman iPSC-derived neuronsmicroelectrode arrayneuronal network developmentretigabine

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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.