A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction

Abstract

De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K + ) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K + currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

“…There is now a growing list of human genetic mutations linking Kv3 channel dysfunction in GABAergic interneurons to a range of debilitating disorders, including AD and epilepsy. Clatot et al [151] used computational modelling of Kv3.2-expressing fast-spiking PV+ GABAergic interneurons to demonstrate how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits resulting in epileptic seizures. In another study by Yeap et al, [152], reduction of potassium channel Kv3.4 levels was shown to ameliorate synapse loss in a mouse model of AD.…”

Mitigating sTNF/TNFR1 activation on VGluT2+ spinal cord interneurons improves immune function after mid-thoracic spinal cord injury

“…Inhibitory, VGat+, interneurons have critical functions in mediating hyperexcitability in the brain (Clatot et al, 2024;Lee & Maguire, 2013), and silencing VGat+ causes detrimental effects during development and disease. Thus, we hypothesized that proper TNFR1 function on VGat+ interneurons in the thoracic spinal cord were necessary to maintain proper immune function.…”