Disorders of the Nervous System
Author: Milagros Lopez | Email: andrmilagroslopez@gmail.com
Milagros Lopez1°2°, Florencia Vassallu1°2°, Laura Caltana3°, Lionel Muller Igaz1°2°
1° Universidad de Buenos Aires, Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas. Buenos Aires, Argentina.
2° CONICET – Universidad de Buenos Aires. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay). Buenos Aires, Argentina.
3° IBCN (CONICET), University of Buenos Aires School of Medicine, Buenos Aires, Argentina
TDP-43 proteinopathy is the primary pathology associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), indicating that these neurodegenerative diseases may have common underlying mechanisms. We have shown that transgenic (Tg) mice conditionally overexpressing a cytoplasmic form of human TDP-43 protein (TDP-43-ΔNLS) in forebrain neurons replicate key features of FTD/ALS, including altered cognitive, motor and social behaviors. Both changes in plasticity-related gene expression and the behavioral phenotypes can be detected 1 month after Tg induction, before overt neurodegeneration occurs. To assess early ultrastructural features in this model, we performed Transmission Electron Microscopy (TEM) analysis in cortex (Ctx) and hippocampus (Hp) of Tg animals and their non-Tg controls. TEM studies (n=4/genotype) of Ctx and Hp revealed that synaptic density was significantly decreased and synapse length was increased in Tg animals. Synaptic cleft thickness was increased and post-synaptic density thickness was decreased only in the Ctx of Tg mice, revealing differential regional effects in synaptic morphology. Lastly, we analysed mitochondrial density and we found an increase in the Ctx and a decrease in the Hp of Tg animals. These alterations in synaptic density and architecture suggest that TDP-43-ΔNLS mice may exhibit deficits in synaptic transmission and that ultrastructural changes may play a role in the behavioral deficits observed in this model.