A novel mouse model of KCNC1 encephalopathy was generated due to the recurrent variant KCNC1-p.A421V. Results indicate that PV-INs - which are known to powerfully control inhibition in the cerebral cortex and specifically express Kcnc1 - are prominently impaired in Kcnc1-p.A421V mice. Analysis of electrophysiological recordings identified a range of cellular defects consistent with potassium channel dysfunction. 

The KCNC1 gene encodes the Kv3.1 subunit of voltage-gated potassium channels, the expression of which is largely prevalent in fast-spiking GABAergic interneurons of the hippocampus and neocortex. The unique kinetic properties of the Kv3.1 channel render it a key contributor to membrane repolarization and the termination of action potentials, enabling neurons to sustain high-frequency firing.

Mutations affecting Kv3 channels can lead to severe neurological conditions, including ataxias, movement disorders, and epilepsies. The A421V (p.Ala421His, c.1262C > T) mutation has been identified as a recurrent KCNC1 variant in patients who present with developmental and epileptic encephalopathy (DEE).

Given that KCNC1 mutations are newly emerging, existing literature on KCNC1 variants is limited. The role of Kv3.1 deficits in interneuron dysfunction is not well understood, nor is the mechanism through which KCNC1 variants and ensuing KV3.1 deficiencies give rise to impaired inhibition and seizure activity. While functional analyses of the A421V mutant have previously been conducted in Xenopus laevis oocytes (Cameron, 2019; Park, 2019), outcomes have proven somewhat inconsistent.

To address this gap and to draw more direct comparisons with human ion channel physiology, we developed a novel mouse model of the A421V variant of KCNC1 epilepsy (Kcnc1-A421V/+). Differences in the inhibitory interneurons of wildtype mice and this new mutant model may provide insight into how the A421V mutation, and in turn, how Kv3.1 dysfunction contributes to hyperexcitability at the circuit level and KCNC1-related epileptic pathologies. 

We performed whole cell electrophysiological recordings in PV-INs (parvalbumin-expressing interneurons) in Layers II/III and Layer IV of the cortex in wildtype and Kcnc1-A421V/+ mice to examine and compare their intrinsic physiological properties. We found distinct aberrations in the physiology of Kcnc1 PV-INs, most notably a significantly slower downstroke velocity and a tendency to undergo depolarization block, features that may be attributed to a major reduction in K+ current density.

KCNC1-related epilepsy does not yet have a cure. While anti-seizure and ‘rescue’ medications can be used to treat seizures of varying types and severities, no specific drug has been proven to have greater efficacy. More invasive approaches may reduce the frequency and severity of seizures, yet largely fail to completely eliminate them. Attaining a better understanding of the mechanistic basis through which Kv3.1 defects lead to deficient interneuron inhibition may reveal potential targets for novel treatments for KCNC1-related disorders altogether.

Since Kv3.1 is also prominently expressed at PV-IN synapses, the intrinsic physiology of the Kcnc1-A421V/+ mutant may affect synaptic excitability. Characteristics of synaptic connectivity between WT and A421V mice can be compared using a technique called ‘multipatching.’ Another key next step is to examine the effects of Kv3-specific modulators on PV-IN physiology.