Abstracts

Rationale: How complex network-level phenomena such as seizures emerge from the activity of individual, defined subsets of interconnected neurons remains a fundamental, yet unsolved, question in epilepsy research. Previous investigations into the mechanisms of epilepsy and the initiation and propagation of seizures have focused either at the micro-level of individual neurons, or at the macro-level of the electroencephalogram (EEG), but the ability to link single neuron dynamics and large-scale EEG has remained limited. To bridge this gap, we study the activity profiles of individual neurons during the transition to a seizure in an experimental mouse model of Dravet syndrome (DS). Methods: DS is a severe childhood-onset epilepsy defined by treatment-resistant and temperature-sensitive seizures along with developmental delay/intellectual disability autism spectrum disorder, and increased rate of seizure-related death, due to loss of function heterozygous mutation of SCN1A encoding the type 1 voltage gated sodium channel alpha subunit Nav1.1. We use two-photon calcium imaging to record the simultaneous activity of hundreds of individual neurons in layer 2/3 of the sensorimotor neocortex in awake head-fixed Scn1a+/- mice that are free to run on a spherical treadmill.  Mice are exposed to passive elevation of core body temperature, inducing a seizure.  We track the activity of individual neurons as body temperature rises and apply methods from topological data analysis and multilayer network community detection to identify and track the evolution of functionally defined cell groups during the transition to the seizure state. Results: We find that although population level statistics describe changes in burst amplitude and frequency during the transition to the seizure state, these results are not truly representative of the underlying cellular behavior.  Instead, we identify functional groups of cells based on similarities between the profiles of their bursting dynamics.  While certain initially quiet cells are progressively recruited into an active state, other groups of cells become increasingly less active as the seizure approaches. Conclusions: Overall, our results reveal that progressive changes in the activity patterns of functionally defined subgroups of neurons play important roles in driving seizure activity. Funding: This work was supported by NSF NCS-FO Award Numbers SMA-1734795 to S.F.M. and SMA-1734813 to E.M.G., and NIH NINDS K08 NS097633 and a Burroughs Wellcome Fund Career Award for Medical Scientists to E.M.G.