Heterozygous expression of a Kcnt1 gain-of-function variant has differential effects on somatostatin- and parvalbumin-expressing cortical GABAergic neurons
Amy N Shore,
Keyong Li,
Mona Safari,
Alshaima'a M Qunies,
Brittany D Spitznagel,
C David Weaver,
Kyle Emmitte,
Wayne Frankel,
Matthew C Weston
Affiliations
Amy N Shore
Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Neurobiology Research, Roanoke, United States; Department of Neurological Sciences, University of Vermont, Burlington, United States
Keyong Li
Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Neurobiology Research, Roanoke, United States
Mona Safari
Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Neurobiology Research, Roanoke, United States; Translational Biology, Medicine, and Health Graduate Program, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, United States
Alshaima'a M Qunies
Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, United States; School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, United States
Brittany D Spitznagel
Department of Pharmacology, Vanderbilt University, Nashville, United States; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States
C David Weaver
Department of Pharmacology, Vanderbilt University, Nashville, United States; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, United States; Department of Chemistry, Vanderbilt University, Nashville, United States
Kyle Emmitte
Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, United States
Fralin Biomedical Research Institute at Virginia Tech Carilion, Center for Neurobiology Research, Roanoke, United States; Department of Neurological Sciences, University of Vermont, Burlington, United States; Translational Biology, Medicine, and Health Graduate Program, Fralin Biomedical Research Institute at Virginia Tech Carilion, Roanoke, United States; School of Neuroscience, Virginia Tech, Blacksburg, United States
More than 20 recurrent missense gain-of-function (GOF) mutations have been identified in the sodium-activated potassium (KNa) channel gene KCNT1 in patients with severe developmental and epileptic encephalopathies (DEEs), most of which are resistant to current therapies. Defining the neuron types most vulnerable to KCNT1 GOF will advance our understanding of disease mechanisms and provide refined targets for precision therapy efforts. Here, we assessed the effects of heterozygous expression of a Kcnt1 GOF variant (Kcnt1Y777H) on KNa currents and neuronal physiology among cortical glutamatergic and GABAergic neurons in mice, including those expressing vasoactive intestinal polypeptide (VIP), somatostatin (SST), and parvalbumin (PV), to identify and model the pathogenic mechanisms of autosomal dominant KCNT1 GOF variants in DEEs. Although the Kcnt1Y777H variant had no effects on glutamatergic or VIP neuron function, it increased subthreshold KNa currents in both SST and PV neurons but with opposite effects on neuronal output; SST neurons became hypoexcitable with a higher rheobase current and lower action potential (AP) firing frequency, whereas PV neurons became hyperexcitable with a lower rheobase current and higher AP firing frequency. Further neurophysiological and computational modeling experiments showed that the differential effects of the Kcnt1Y777H variant on SST and PV neurons are not likely due to inherent differences in these neuron types, but to an increased persistent sodium current in PV, but not SST, neurons. The Kcnt1Y777H variant also increased excitatory input onto, and chemical and electrical synaptic connectivity between, SST neurons. Together, these data suggest differential pathogenic mechanisms, both direct and compensatory, contribute to disease phenotypes, and provide a salient example of how a pathogenic ion channel variant can cause opposite functional effects in closely related neuron subtypes due to interactions with other ionic conductances.
