title: Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex.
abstract: 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.
authors.affiliation: Program in Human and Molecular Genetics, UT Health, Houston, TX, USA.
authors.forename: R Michelle
authors.initials: RM
authors.lastname: Reith
authors.forename: James
authors.initials: J
authors.lastname: McKenna
authors.forename: Henry
authors.initials: H
authors.lastname: Wu
authors.forename: S Shahrukh
authors.initials: SS
authors.lastname: Hashmi
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: Cho
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D014402:Tuberous Sclerosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins