From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis

J Intellect Disabil Res. 2009 Oct;53(10):838-51. doi: 10.1111/j.1365-2788.2009.01208.x. Epub 2009 Aug 19.


Background: Tuberous sclerosis (TSC) is a multi-system disorder caused by heterozygous mutations in the TSC1 or TSC2 gene and is often associated with neuropsychiatric symptoms, including intellectual disability, specific neuropsychological deficits, autism, other behavioural disorders and epilepsy.

Method: Here, we review evidence from animal models of TSC for the role of specific molecular and cellular processes in the pathogenesis of cognitive, developmental and epilepsy-related manifestations seen in the disorder.

Results: Recent evidence shows that, in animal models, disinhibited mTOR (mammalian target of rapamycin) signalling substantially contributes to neuropsychiatric phenotypes, including cognitive deficits and seizures. We discuss potential pathogenetic mechanisms involved in the cognitive phenotypes of TSC and present implications regarding mTOR inhibitor-based treatments for TSC-related neuropsychiatric features.

Conclusions: Results suggest that reversing the underlying molecular deficits of TSC with rapamycin or other mTOR inhibitors could result in clinically significant improvements of cognitive function and neurological symptoms, even if treatments are started in adulthood.

Publication types

  • Review

MeSH terms

  • Animals
  • Behavior, Animal
  • Carrier Proteins / genetics*
  • Cell Biology*
  • Cognition Disorders / complications
  • Cognition Disorders / genetics*
  • Cognition*
  • Disease Models, Animal
  • Epilepsy / complications
  • Epilepsy / genetics
  • Humans
  • Mice
  • Molecular Biology / methods*
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Rats
  • Risk Factors
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis / complications
  • Tuberous Sclerosis / genetics*


  • Carrier Proteins
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse