03/07/2025
Loss-of-function mutations in the TSC1 gene (which stands for tuberous sclerosis 1) often cause autism spectrum disorder. In rodent models, if we selectively delete this Tsc1 gene only from Purkinje neurons in the mouse cerebellum, those mice exhibit several autism-like behaviors.....including problems with social interaction, motor coordination, and exaggerated repetitive behaviors. This makes for an interesting research model because we can study how deleting a single gene...like Tsc1..from a single type of neuron....cerebellar Purkinje neurons..... causes behavioral problems associated with autism. Using this mouse model, we studied how the electrical activity of these Tsc1-deficient Purkinje neurons changes and the reasons for those changes. We found that Tsc1-deficient Purkinje neurons have significantly reduced electrical activity, and that this impaired electrical activity is caused by a loss of sodium channels at the axon initial segment (AIS). The AIS of Purkinje neurons is where these cells' electrical signals (action potentials) are first generated. Finally, we showed that the AIS of Tsc1-deficient Purkinje neurons are also missing ankyrin G. Ankyrin G is a protein that serves to organize and localize all the proteins necessary to build a functional AIS. So, with no ankyrin G, it makes sense the sodium channels are missing, and with no sodium channels, these cells cannot generate action potentials in a normal manner. Combined, this study shows why losing Tsc1 in Purkinje neurons destroys these cells' typical electrical activity, which is what causes the autism-like behavioral problems in these mice.
