Abstracts

Rationale: Among the multitude of comorbidities arising from Alzheimer’s Disease (AD), the heightened risk of seizures is increasingly recognized. Reports indicate that around 8-10% of AD patients have epilepsy. Epilepsy influences disease progression and cognitive decline in AD patients while AD pathology may exacerbate seizure burden; therefore, developing strategies to suppress seizures is vital to the treatment of AD. Like many AD models, the TgF344-AD rat, expressing both mutant human APP and PSEN1, shows non-convulsive spike and wave discharges (SWD). We have previously reported that optogenetic activation of the deep and intermediate layers of the superior colliculus (DLSC) suppress SWDs in “pure” epilepsy models. Thus, we aimed to determine if activation of DLSC would suppress seizures in the TgF344-AD model. Second, we examined the interaction between status epilepticus (SE) and AD pathology in the same model.

Methods: Optogenetic Activation of the DLSC: Adult (9m) male and female TgF344-AD rats were used. We injected virus coding for channelrhodopsin-2 (ChR2) into the DLSC of rats, implanted fiber optics, and cortical EEG electrodes. We then compared continuous neuromodulation to that of on-demand neuromodulation (real time detection of seizures) paradigms across three frequencies (5,20,100Hz). We quantified the number and duration of each SWD during each two-hour-long trial.
_x000D_ SE Induction: Male and female TgF344-AD rats and wild-type littermates were used and split into 4 groups [AD-Saline, AD-SE, WT-Saline, WT-SE]. Pilocarpine or saline was injected at 4.5 months of age. 6 months after SE spatial memory was tested using the Morris Water Maze. After behavioral testing, cortical EEG screws were implanted and all rats underwent 48hrs of chronic EEG monitoring. Brains were processed for histological evaluation of AD pathology.

Results: We unexpectedly found that discharges in the TgF344-AD rat differed from SWDs observed in typical absence epilepsy models. We identified two types of SWDs – Type I discharges had typical generalized, bilaterally synchronous onset and offset. Type II had unilateral onset, occasional periods of bilateral synchronization, and periods of only unilateral activity. Activation of the DLSC produced indeterminant effects when both seizure types were grouped together, but ongoing analysis assessing the impact on Type I vs. Type II seizures may reveal a different pattern. Behavioral deficits were evident in the MWM. As expected, SE resulted in deficits. Likewise, AD genotype resulted in subtle deficits. No genotype by SE interaction was found, likely due to an SE derived floor effect. 48hr chronic EEG recordings also revealed Type I and Type II seizures, and emergence (as expected) of limbic seizures after SE.

Conclusions: TgF344-AD rats display novel seizure types, each of which may be targetable through optogenetic activation of the DLSC. Additionally, SE induction exacerbates cognitive decline in both AD and WT rats, finding ways to treat both seizure types may reverse deficits and pathological severity.

Funding: TL1TR001431, ARCS/MWC Scholar, NINDS R01- 1R01NS097762 / 1R01NS097762-05S1 (PAF)