A role of dentate gyrus mechanistic target of rapamycin activation in epileptogenesis in a mouse model of posttraumatic epilepsy

Epilepsia. 2024 Jul;65(7):2127-2137. doi: 10.1111/epi.18011. Epub 2024 May 18.


Objective: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI.

Methods: An adeno-associated virus (AAV)-Cre viral vector was injected into the hippocampus of Rptorflox/flox (regulatory-associated protein of mTOR) mutant mice to inhibit mTOR activation in dentate gyrus granule cells. Four weeks after AAV-Cre or AAV-vehicle injection, mice underwent CCI injury and were subsequently assessed for mTOR pathway activation by Western blotting, neuronal death, and mossy fiber sprouting by immunopathological analysis, and posttraumatic seizures by video-electroencephalographic monitoring.

Results: AAV-Cre injection primarily affected the dentate gyrus and inhibited hippocampal mTOR activation following CCI injury. AAV-Cre-injected mice had reduced neuronal death in dentate gyrus detected by Fluoro-Jade B staining and decreased mossy fiber sprouting by ZnT3 immunostaining. Finally, AAV-Cre-injected mice exhibited a decrease in incidence of PTE.

Significance: mTOR pathway activation in dentate gyrus granule cells may at least partly mediate pathological abnormalities and epileptogenesis in models of TBI and PTE. Targeted modulation of mTOR activity in this hippocampal network may represent a focused therapeutic approach for antiepileptogenesis and prevention of PTE.

Keywords: Raptor; hippocampus; mice; rapamycin; seizure.

MeSH terms

  • Animals
  • Brain Injuries, Traumatic / complications
  • Brain Injuries, Traumatic / metabolism
  • Brain Injuries, Traumatic / pathology
  • Dentate Gyrus* / metabolism
  • Dentate Gyrus* / pathology
  • Disease Models, Animal*
  • Electroencephalography
  • Epilepsy, Post-Traumatic* / etiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mossy Fibers, Hippocampal / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • TOR Serine-Threonine Kinases* / metabolism


  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse