Abstracts

Rationale: The development of epilepsy and its cognitive comorbidities can be influenced by both genetic and environmental factors. In the stargazer mouse model of absence epilepsy with a mutation in Cacng2, homozygous mutant mice have absence epilepsy while heterozygous mice do not. In addition, sensory deprivation via whisker trimming during development can significantly exacerbate the total burden of absence seizures. Here, we evaluate the effect of whisker trimming versus sham trimming on wild type, heterozygous, and homozygous Cacng2 mutant mice.

Methods: Cacng2 mice were randomly selected for whisker trimming or sham trimming from postnatal day 5 (P5) to P30. After P60, mice were anesthetized with isoflurane and surgically implanted with electrodes in bilateral frontal (M2) and posterior parietal regions for EEG recording. EEG data was analyzed using EEGLAB and Brainstorm in MATLAB to compare seizure duration, theta to gamma phase-amplitude coupling (TG-PAC) and theta to high gamma phase-amplitude coupling (THG-PAC) between trim and sham male and female mice across the three genotypes. Whisker-trim and sham-trim male mice were then trained through the 5-Choice Serial Reaction Time Task (5-CSRTT) to assess the effects of genotype and sensory deprivation on sustained attention.

Results: The seizure duration of whisker-trim heterozygous mice was significantly greater than that of sham-trim heterozygous mice and all wild-type mice cohorts (n=9-18/cohort). The seizure duration of the sham-trim heterozygous mice and the wild-type cohorts did not significantly differ from each other. Neither bilateral TG-PAC nor bilateral THG-PAC was significantly different between any of the cohorts. However, right parietal TG-PAC and THG-PAC were significantly greater than that of the left parietal lobe overall (p=0.005 and p=0.023, respectively, Wilcoxon test). In addition, there was no significant difference between male and female mice. Pilot studies from 2 whisker-trim homozygous mutant mice and 3 whisker-trim heterozygous mice during the 5-CSRTT show a right parietal theta power (6-10 Hz) peak in the pre-stimulus period (0-400ms prior to stimulus onset) prior to a correct response. This anticipatory rise in theta power is absent in the homozygous mutant mice; rather, there is a rise in theta power only after stimulus onset in the setting of a correct response. With incorrect responses, the pre-stimulus and post-stimulus right parietal theta responses for heterozygous and homozygous mutant mice, respectively, trended at lower levels.

Conclusions: These findings suggest that neither sensory deprivation nor a single mutant allele of Cacng2 is sufficient to cause epilepsy alone. However, when sensory deprivation is performed in Cacng2 heterozygous mice, the combination is sufficient to induce absence epilepsy. Failure to increase theta power in the right posterior parietal lobe may be related to an inability to sustain task-related attention. However, further investigation is needed to fully determine how sensory deprivation affects background oscillations, seizures, and sustained attention with increasing doses of a mutant allele.

Funding: Please list any funding that was received in support of this abstract.: NINDS K08 NS096029, Nancy Chang Award, NARSAD Young Investigator Award.