206 | Assessment of acute and chronic treatment with the potassium channel blocker 4-AP on behavioral deficits displayed by a TDP-43 transgenic model of ALS/FTD

Disorders of the Nervous System

Author: María Florencia Vassallu | Email: florencia.vassallu@gmail.com

Florencia Vassallu 1°2°, Milagros López 1°2°, Lionel Muller Igaz 1°2°

1° Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas. Grupo de Neurociencia de Sistemas. Buenos Aires, Argentina.
2° CONICET – Universidad de Buenos Aires. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay). Buenos Aires, Argentina.

TDP-43 is the main component of the pathological cytoplasmic inclusions found in two incurable neurodegenerative diseases, amyotrophic lateral sclerosis and frontotemporal dementia. This nuclear protein is involved in RNA metabolism, among other functions. Our transgenic mice with inducible cytoplasmic expression of TDP-43 in forebrain neurons recapitulate behavioral phenotypes, neurodegeneration and gene expression changes that occur in both diseases. We recently described in these animals a reduction in cellular and global brain activity. In order to investigate a potential causal link between this decrease and the profound behavioral phenotypes observed in this model, we evaluated the effect of acute and chronic systemic injection of the FDA-approved neuronal activity enhancer drug 4-Aminopyridine (4-AP). In the acute protocol, animals were tested in the different tasks 3 hs after 4-AP injection at 1-month post transgene induction, while in the chronic protocol the injection occurred daily during 30 days before testing. Transgenic animals subjected to the acute protocol showed similar deficits in spatial and working memory (Y-maze), locomotion and exploratory behavior (Open Field) and spasticity (clasping) as those injected with vehicle. Preliminary experiments using the chronic protocol suggest a partial recovery of some these deficits. These results indicate that a persistent activity-inducing treatment might be useful as a potential therapy for these pathologies.