This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Absence seizures are characterized by an abrupt onset of synchronous spike wave discharges (SWDs) across widespread cortical areas and the impairment of consciousness. They depend on both cortical and thalamic networks, requiring the coordination of millions of neurons to fire synchronously across networks with different intrinsic firing rates and connectivity. A large gap exists in our understanding of the temporal ordering of the dynamic firing rate changes across the different functional hierarchies of these populations. In particular, the temporal ordering of these changes may point to specific means of seizure control. Methods: We used multiple high density silicon probes (832 recording sites) in awake head fixed mice to concurrently measure the firing dynamics across cortical and thalamic functional hierarchies in the Scn8a heterozygous loss of function mouse model of absence epilepsy (N=3 mice, 7 seizures/mouse). We measured the firing rates and population spike synchrony simultaneously in primary sensory cortex/first order relay thalamus: primary somatosensory cortex (SSC) and ventrobasal thalamus (VB) and in higher order/multisensory integration cortical and thalamic populations: orbitofrontal association cortex (OFA), posterior parietal association cortex (PPA), and posterior/lateroposterior thalamic nuclei (PO/LP). Results: We found that all populations we measured exhibited increases in synchronous firing aligned with the spike portion of the SWDs. OFA cortex exhibited the weakest maximum population spike synchrony, measured by mean phase coherence (MPC), (MPC=0.42+/-0.02 Arb. Units) and had the latest onset of seizure as measured by ECOG of the populations measured (+423 ms relative to the average across sites). The population that exhibited the highest synchronization was PO/LP (MPC=0.59+/-0.01) and it exhibited the only significant increase in synchrony that was detectable before seizure onset (0.44 +/- 0.02 Arb Units at -4s relative to seizure onset P< 0.05). Interestingly, each population we measured exhibited a population specific change in firing rate (both increases and decreases in rate) that converged to a common mean frequency between populations at seizure onset. An 18% decrease in mean firing rate in PO/LP was observed at 10s prior to seizure onset (P< 0.01) and PO/LP exhibited the highest change at seizure onset (-58% decrease, P< 0.01). In contrast, VB exhibited the highest increase in firing rate at seizure onset (+25%, P< 0.05). Conclusions: Spike synchronization requires that neurons either adjust their firing frequencies to be of a similar frequency or to cluster their spikes in ways to enhance their overlap. We find here that that neurons across different brain areas each uniquely adjust their firing frequencies towards a common mean frequency. This suggests the presence of an underlying dynamical or other globally acting mechanism by which neurons adjust their mean firing rates to support synchronization, which we find to be the most robust in PO/LP. Targeting such mechanisms may be a novel means of understanding and controlling generalized epilepsies. Funding: Please list any funding that was received in support of this abstract.: This work was supported by (Epilepsy training grant #) to JMH and (R01 #) to JRH.
