ONLINE: Cellular/circuit dysfunction in a model of Dravet syndrome - a severe childhood epilepsy.
THIS TALK IS NOW AN ONLINE SEMINAR (100 places) https://zoom.us/j/7644908050
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.
Date: 17 March 2020, 14:00
Venue: https://zoom.us/j/7644908050
Speaker: Ethan M. Goldberg, MD, PhD (The Children's Hospital of Philadelphia)
Organiser: Dr Chaitanya Chintaluri (University of Oxford)
Host: Dr Tim Vogels
Topics:
Booking required?: Not required
Audience: Members of the University only
Editor: Chaitanya Chintaluri