Cellular/circuit dysfunction in a model of Dravet syndrome - a severe childhood epilepsy
Prof
The Children's Hospital of Philadelphia
Event Information
Host
The Neurotheory Forum
Duration
70 minutes
Abstract
Dravet syndrome is a severe childhood epilepsy due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage gated sodium (Na+) channel alpha-subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) at early developmental time points indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons (INs) and, in particular, in parvalbumin-positive fast-spiking basket cells (PV-INs). This has led to a model of Dravet syndrome pathogenesis whereby Nav1.1 mutation leads to preferential IN dysfunction, decreased synaptic inhibition, hyperexcitability, and epilepsy. We found that, at later developmental time points, the intrinsic excitability of PV-INs has essentially normalized, via compensatory reorganization of axonal Na+ channels. Instead, we found persistent and seemingly paradoxical dysfunction of putative disinhibitory INs expressing vasoactive intestinal peptide (VIP-INs). In vivo two-photon calcium imaging in neocortex during temperature-induced seizures in Scn1a+/- mice showed that mean activity of both putative principal cells and PV-INs was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice immediately prior to seizure onset. We suggest that impaired PV-IN synchronization, perhaps via persistent axonal dysfunction, may contribute to the transition to the ictal state during temperature induced seizures in Dravet syndrome.
Topics
Related Seminars
Deciphering the Dynamics of the Unconscious Brain under General Anesthesia
Stanford Neurosciences Seminar Series talk by Emery Brown (Massachusetts Institute of Technology, Neuroscience Statistics Research Lab) on deciphering the dynamics of the unconscious brain under…
Engineering human myelination in vitro: Mechanobiologically compatible platforms for CNS drug discovery
UCL Department of Neuroinflammation Seminar by Professor Emad Moeendarbary (Professor of Cell Mechanics and Mechanobiology, UCL Mechanical Engineering) on how biophysical factors such as substrate…
Colloquium on the Brain and Cognition with Christopher Harvey, PhD, Harvard University
Picower Institute Colloquium on the Brain and Cognition featuring Christopher Harvey, PhD, of Harvard University, held in Singleton Auditorium (46-3002) at MIT Building 46, 43 Vassar Street.
Related Job Opportunities
PhD Studentship: Mitochondrial Metabolism and Novel Therapeutic Strategies for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) (Fixed Term)
Supervisors: Professor Andrew Murray, Department of Physiology, Development and Neuroscience, University of Cambridge Dr Ross Lindsay, Novo Nordisk Funding: Fully funded PhD studentship (Home/UK…
Research Associate (Fixed Term)
We seek a highly motivated Postdoctoral Research Associate to join the laboratory of Professor Kathy Niakan. We are based in the Loke Centre for Trophoblast Research (LCTR), in the Department of…
Research Assistant/Associate (Fixed Term)
Applications are invited for a postdoctoral research associate position to study the neural mechanisms of visual learning in mice, in the laboratories of Professor Ole Paulsen and Dr Jasper Poort…