Authors :
Presenting Author: Samiksha Chopra, BS – Yale University
Stefan Sumsky, PhD – Yale University School of Medicine
Yang Zheng, MD, PhD – Yale
Jiayang Liu, PhD – Yale University
Hal Blumenfeld, MD, PhD – Yale University
Rationale:
Spike-and-wave discharges (SWDs) are hallmark features of absence seizures, a generalized seizure type characterized by brief lapses in consciousness and most often observed in pediatric populations. The mechanisms contributing to impaired consciousness during these episodes remain elusive, in part due to the limited availability of suitable animal models for detailed investigations. Since performing a behavioral task requires at least minimal levels of arousal and attentional engagement, such tasks can serve as indirect measures of consciousness. Prior studies in rats have demonstrated that behavioral impairments during SWDs parallel those observed in human patients. In this work, we aimed to design a lick-on-click behavioral task in mice to create an experimental framework suitable for probing disrupted cortical networks associated with impaired behavioral responses.
Methods:
2 - 3 months old male and female mice from three genetic strains of absence epilepsy (C3H/HeJ, HEJ/FEJ, and SCN8A) were implanted with tripolar intracranial EEG electrodes in the frontal and parietal cortices. A ground electrode was placed mid-cerebellum. Following 1 week of recovery, the mice began a standard water restriction protocol. For behavioral training and recordings, the mice were placed in a head-fixed position on a running wheel and trained to respond to an auditory click by licking a water reward (totaling 278 recording sessions from 12 mice).
Results:
We found that baseline SWD frequencies varied by genotype: C3H/HeJ mice exhibited 11.55 SWDs/hr (n=3), HEJ/FEJ mice 0.93 SWDs/hr (n=3), and SCN8A mice 105.72 SWDs/hr (n=6). In SCN8A mice, extended water restriction, used to motivate task performance, was associated with a substantial reduction in SWD frequency. However, SWD activity could be reinstated by increasing both the duration spent on the wheel and the variability in cue timing. Notably, water restriction reduced SWD frequency across all three models.
Conclusions:
This behavioral paradigm, combined with future cortical circuit-level recording approaches, offers a valuable tool for dissecting the neural dynamics underlying behavioral unresponsiveness during SWDs. Ultimately, these insights may illuminate core biological mechanisms responsible for impaired consciousness in epilepsy, paving the way for better-targeted therapeutic interventions.
Funding:
NIH/NINDS R37NS100901