Abstracts

Rationale: For 25 years, Alzheimer s disease (AD) has been recognized as a clinical risk factor for late onset seizures. AD and epilepsy share similar atrophic and metabolic changes in the human brain and most familial AD gene mutations lead to epilepsy. In addition, multiple AD mouse models overexpressing amyloid beta exhibit spontaneous seizures as well as remodeled circuitry similar to that seen in epilepsy. Aggregation of the microtubule binding protein tau is one hallmark of AD and recent work implicates a role for tau in AD seizure phenotypes. Deletion of the MAPT gene, which encodes tau, suppresses seizures and normalizes the synaptic excitation/inhibition imbalance in the J20 AD mouse model, suggesting that tau regulates hyperexcitability in AD mice (Roberson et al., 2011). Here we examined the role of tau in the non-AD nervous system using genetic knockout of tau in both mouse and Drosophila models of hyperexcitability.Methods: Double mutant mice with Kcna1-/- and either tau-/-, tau+/- or tau+/+ alleles were analyzed by in-vivo EEG recording for 9 hours and seizures were counted to determine the effect of tau loss on Kcna1-/- hyperexcitability. Survival up to 10 weeks of age was also monitored in these double mutants. Kcna1-/-tau+/+, Kcna1-/-tau-/-, Kcna1+/+tau-/- and Kcna1+/+tau+/+ mice were imaged by MRI and hippocampal volumes were determined by tracing in both coronal and sagittal planes (Amira 3.1). Bang sensitive Drosophila mutants (kcc and eas) with tau disruption by tau^EP3203 and/or Df(3R)MR22 as well as tau+/+ controls were tested 1-2 days post-eclosion for the presence of paralysis and seizure evoked by 10 seconds of vortexing.Results: Kcna1-/- mice have severe spontaneous seizures, early lethality, and megencephaly. We observed by in-vivo EEG recordings that double mutant Kcna1-/- mice with either tau+/- or tau-/- alleles have significantly fewer seizures compared to Kcna1-/-tau+/+ mice (n=8, p<0.05). Homozygous tau knockout in Kcna1-/- mice also rescued the early lethality of this seizure mutant from 30 to 75 percent survival at 10 weeks of age (n=20, p<0.05). Additionally, preliminary MRI analysis suggests that hippocampal volume in Kcna1-/-tau-/- mice is decreased compared to Kcna1-/-tau+/+, rescuing the developmental phenotype. As a second model of hyperexcitability, bang sensitive Drosophila mutants display low thresholds for induced paralysis and seizures. We observed that tau reduction in both kcc and eas mutants significantly decreased paralysis and seizures (kcc: n?87, p<0.05; eas: n?98, p<0.01).Conclusions: Our results provide the first evidence that tau plays a constitutive role in the regulation of excitability in the non-AD nervous system. Tau protein is known to affect many cellular processes, ranging from microtubule transport to signal transduction. While the molecular mechanism remains to be defined, the effects of tau loss on excitability extend beyond the reversal of amyloid beta-induced AD phenotypes to encompass a role in the expression of epilepsy, where tau s function can also be explored as a future therapeutic target.