Authors :
Presenting Author: Patrick Lawlor, MD, PhD – Children's Hospital of Philadelphia
Eric Wengert, PhD – Children's Hospital of Philadelphia
Vijay Balasubramanian, PhD – University of Pennsylvania
Ethan Goldberg, MD, PhD – CHOP
Rationale:
Dravet Syndrome (DS) is a severe neurodevelopmental disorder caused by pathogenic variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1 that is preferentially expressed in inhibitory interneurons. Clinically, DS is associated with treatment-resistant epilepsy, developmental delay, autism spectrum disorder, sudden unexplained death in epilepsy (SUDEP), and temperature-sensitive seizures. While inhibitory interneuron dysfunction (failure of inhibition) would be expected to increase the tendency for seizures overall, the specific mechanism(s) leading to the preponderance of febrile seizures in DS are poorly understood. Recent experimental data from our group has shown that, in vitro, elevated temperature modulates sodium and potassium currents to cause selective action potential failure in Scn1a+/- parvalbumin-positive interneurons (PV-INs). Here, we extend a classic computational model of a fast-spiking interneuron to model these effects.
Methods:
We extended the single-compartment Hodgkin-Huxley model of a fast-spiking interneuron developed by Wang and Buzsaki to include temperature-dependent effects which were found in our group’s experiments. Specifically, experiments showed that: 1) the rate of potassium current activation increased with hyperthermia; 2) the rate of sodium current inactivation increased with hyperthermia, and 3) the effective conductance of sodium current decreased with hyperthermia. We modeled these effects using a simple Q10-based approach and fit the model to the experimental data. For the model’s unknown parameters (sodium and potassium conductance values), we inferred optimal values using a Bayesian approach. In ongoing work, we incorporate temperature dependence into a circuit model and explore both circuit excitability, and the transition into the seizure state as a function of increasing temperature.
Results:
Our minimalistic model of a PV-IN was able to reproduce the experimentally-observed effects: 1) selective failure of action potential generation in Scn1a+/- PV-INs, but not wild type (WT) PV-INs, with elevated temperature in the physiological range; and 2) that hyperthermia-related action potential generation could be rescued by partial blockade of potassium current. Our model suggests that the most important temperature-dependent components contributing to action potential failure are (in decreasing order): increased rate of potassium current activation; decreased sodium conductance; and increased rate of sodium current inactivation.
Conclusions:
We present a minimalistic model of a DS PV-IN which incorporates newly-identified effects of temperature on sodium and potassium currents, and which reproduces temperature-dependent failure of action potential generation. Our model links biophysical changes in ion channel properties to core features of the human disease, and may inform future therapeutic interventions for temperature-sensitive seizures in DS and beyond.
Funding:
NIH NINDS UE5NS065745 and Holt Family Epilepsy Neurogenetics Fellowship to P.N.L.; NIH NINDS R01NS110869 and R01137604 to E.M.G.; NIH NINDS F32NS126234 to EW; NIH NIDCD R01DC017690 to VB.