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:

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.