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

Neurobiol Dis. 2013 Mar;51:93-103. doi: 10.1016/j.nbd.2012.10.014. Epub 2012 Nov 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Child
  • Child Development Disorders, Pervasive / genetics
  • Child Development Disorders, Pervasive / metabolism
  • Child Development Disorders, Pervasive / physiopathology
  • Disease Models, Animal
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology
  • Tuberous Sclerosis / genetics
  • Tuberous Sclerosis / metabolism
  • Tuberous Sclerosis / physiopathology*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / deficiency*
  • Tumor Suppressor Proteins / genetics

Substances

  • TSC2 protein, human
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins