PROJECT SUMMARY
I am applying for this NRSA postdoctoral fellowship with the long-term career goal of becoming an
independent investigator capable of leading a highly productive research lab in the field of neuroscience. Under
the guidance of Dr. Ethan Goldberg and Dr. Doug Coulter, this mentored fellowship will provide me the
conceptual and hands-on training required to achieve my goal and thrive in the scientific enterprise.
Pathogenic variants in the gene KCNC1, which encodes the voltage-gated potassium channel subunit
Kv3.1, lead to severe neurological disease including epilepsy. While most patient-derived variants are loss-of-
function, the precise mechanisms by which impaired Kv3.1 function alters individual neuron physiology and
neural circuit function to result in spontaneous seizures are unclear. Kv3.1 is prominently expressed in
parvalbumin-positive fast-spiking inhibitory interneurons (PV-IN) in various subcellular regions including the
dendrites, soma, axon, and synaptic terminal where it critically contributes to reliable high-frequency action
potential generation and propagation. Because PV-INs critically contribute to network dynamics and constrain
excitability of nearby excitatory pyramidal neurons in cortical circuits, we hypothesize that Kv3.1 dysfunction
impairs PV-IN high-frequency action potential generation and propagation, disinhibits pyramidal neurons, and
contributes to aberrant network excitability to drive abnormal behavior and seizures. Therefore, the overarching
objective of this study is to determine the effect of mutant Kv3.1 on PV-IN physiology as a potential major
contributor to pathogenesis of KCNC1-related epilepsy. In aim 1, I will collect patch-clamp electrophysiology
recordings of somatic and axonal potassium channel function and neuronal excitability in PV-INs from a novel
mouse model of KCNC1 epilepsy which harbors the epileptic encephalopathy patient-derived p.A421V variant.
Given the substantially reduced channel activity observed in the p.A421V variant, and that Kv3 currents are
necessary for fast-spiking physiology, I anticipate that PV-INs from the mouse model of KCNC1 epileptic
encephalopathy will exhibit impaired action potential generation at the soma, and unreliable propagation through
the axon. In aim 2, I will interrogate deficits in inhibitory synaptic transmission in response to mutant Kv3.1
expression using multiple (6-8) simultaneous recordings of synaptically-connected PV-INs and pyramidal
neurons in cortical microcircuits. Lastly, in aim 3 I will corroborate my in vitro findings in the in vivo context
through calcium-imaging of neuronal activity in awake, behaving mice. To relate neuronal activity to relevant
behavior, I will examine the excitability of both cortical pyramidal neurons and PV-INs in response to sensory
stimulation by whisker deflection and test the hypothesis that altered Kv3.1 function in PV-INs compromises
network inhibition in vivo. Overall, completion of the aims described in this mentored fellowship will provide
significant insight into the mechanisms of epilepsy in KCNC1-related disorders and deeper understanding of the
contribution of Kv3 channels to PV-IN physiology in general.