Abstract Details

Title Role of Seizures in Behavioral Deficits and Neurodegeneration in rNLS8 Mice

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P11 - Poster Session 11 (8:00 AM-9:00 AM)

Poster/Presentation
Number 11-033

Objective To determine whether seizures contribute to behavior deficits and neurodegeneration in the rNLS8 TDP-43 mouse model of ALS.

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized, in over 90% of cases, by cytoplasmic aggregates of the primarily nuclear RNA binding protein, TDP-43. Recent reports in mouse models suggest TDP-43 pathology induces complex alterations in neuronal excitability that may promote neurodegeneration via excitotoxicity. Previously, we identified the presence of tonic-clonic seizures in the dox-regulatable rNLS8 mouse model of ALS. These mice ectopically express human TDP-43 with a non-functional nuclear localization signal (hTDP-43?NLS) throughout the brain and spinal cord under the NEFH promoter. Interestingly, in our preliminary studies, approximately 33% of rNLS8 mice did not develop seizures even into late disease stages. The mechanism(s) underlying heterogenous epileptogenesis in rNLS8 mice remains unknown. To begin to answer this question, we used continuous screw-electrode EEG, behavioral assays, and histology to identify distinguishing phenotypic characteristics between seizure(+) and seizure-free mice.

Design/Methods Adult rNLS8 mice (n=15) were implanted with unilateral skull screw-electrodes and connected to a tethered EEG system for 3–4 weeks continuous recording after transgene induction. A behavioral battery was performed at baseline and after the recording period prior to tissue collection. EEGs were analyzed by automated seizure detection software (Sirenia Pro) and all seizure-candidate events were confirmed manually.

Results

Mean latency to seizure onset was approx. 2.6 weeks off-DOX (n=11 seizure(+), n=4 seizure-free). Interestingly, we observed a modest reduction in exploration in seizure(+) mice on Y maze (num. entries, p=0.04). However, no differences were observed in spatial memory (% alternations, Y maze), anxiety behavior (elevated zero maze), or histological markers of hippocampal TDP-43 pathology, astrogliosis, and microgliosis.

Conclusions Seizures(+) and seizure-free rNLS8 mice were largely indistinguishable on gross behavioral and histological examination. However, a larger sample size is needed to reach more conclusive findings.

Authors/Disclosures
Jaskeerat Gujral, BA PRESENTER	Mr. Gujral has nothing to disclose.
William Rodemer, PhD	Dr. Rodemer has nothing to disclose.
Elizabeth Jia	Miss Jia has nothing to disclose.
Samuel Rekulak	Mr. Rekulak has nothing to disclose.
Halvor Juul, PhD	Dr. Juul has nothing to disclose.
Irene Ra, BA	Ms. Ra has nothing to disclose.
silvia porta, PhD	Miss porta has nothing to disclose.
Delia Maria Talos, MD	The institution of Dr. Talos has received research support from NIH. Dr. Talos has received personal compensation in the range of $0-$499 for serving as a Scientific reviewer with NIH. Dr. Talos has received personal compensation in the range of $0-$499 for serving as a Scientific reviewer with DOD.
Virginia Lee, PhD (University of Pennsylvania)	Virginia Lee, PhD has nothing to disclose.

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