title: Genetic activation of mTORC1 signaling worsens neurocognitive outcome after traumatic brain injury.
abstract: Although the mechanisms that contribute to the development of traumatic brain injury (TBI)-related deficits are not fully understood, it has been proposed that altered energy utilization may be a contributing factor. The tuberous sclerosis complex, a heterodimer composed of hamartin/Tsc-1 and tuberin/Tsc-2, is a critical regulatory node that integrates nutritional and growth signals to govern energy using processes by regulating the activity of mechanistic Target of Rapamycin complex 1 (mTORC1). mTORC1 activation results in enhanced protein synthesis, an energy consuming process. We show that mice that have a heterozygous deletion of Tsc2 exhibit elevated basal mTORC1 activity in the cortex and the hippocampus while still exhibiting normal motor and neurocognitive functions. In addition, a mild closed head injury (mCHI) that did not activate mTORC1 in wild-type mice resulted in a further increase in mTORC1 activity in Tsc2(+/KO) mice above the level of activity observed in uninjured Tsc2(+/KO) mice. This enhanced level of increased mTORC1 activity was associated with worsened cognitive function as assessed using the Morris water maze and context discrimination tasks. These results suggest that there is a threshold of increased mTORC1 activity after a TBI that is detrimental to neurobehavioral performance, and interventions to inhibit excessive mTORC1 activation may be beneficial to neurocognitive outcome.
authors.affiliation: 1 Department of Neurobiology and Anatomy, the University of Texas Medical School , Houston, Texas.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rozas
authors.forename: John B
authors.initials: JB
authors.lastname: Redell
authors.forename: Julia L
authors.initials: JL
authors.lastname: Hill
authors.forename: James
authors.initials: J
authors.lastname: McKenna
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Moore
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000378:metabolism*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: AMPK; S6; concussion; mTBI; mTOR; memory