Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. We have generated and characterized a novel TSC mouse model with Purkinje cell specific Tsc2 loss. These Tsc2f/−;Cre mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well reported postmortem finding in patients with ASD, we conducted a series of behavior tests to asses if Tsc2f/−;Cre mice displayed autistic-like deficits. Tsc2f/−;Cre mice demonstrated increased repetitive behavior as assessed with marble burying activity. Using the three chambered apparatus to asses social behavior, we found that Tsc2f/−;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. We also detected social deficits in Tsc2f/f;Cre mice, suggesting that Purkinje cell pathology is sufficient to induce ASD-like behavior. Importantly, social behavior deficits were prevented with rapamycin treatment. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a Tsc2-haploinsufficient background leads to autistic-like behavioral deficits. These studies provide compelling evidence that Purkinje cell loss and/or dysfunction may be an important link between TSC and ASD as well as a general anatomic phenomenon that contributes to the ASD phenotype.

► Mice have social behavioral deficits following Tsc2-mediated Purkinje cell loss.
► Rapamycin treatment prevents social behavior deficits.
► Mild social deficits occur in a Tsc2 haploinsufficient environment.
► Purkinje cell loss leads to increased repetitive behaviors.