Impact of rapamycin on status epilepticus induced hippocampal pathology and weight gain

Exp Neurol. 2016 Jun;280:1-12. doi: 10.1016/j.expneurol.2016.03.015. Epub 2016 Mar 17.

Abstract

Growing evidence implicates the dentate gyrus in temporal lobe epilepsy (TLE). Dentate granule cells limit the amount of excitatory signaling through the hippocampus and exhibit striking neuroplastic changes that may impair this function during epileptogenesis. Furthermore, aberrant integration of newly-generated granule cells underlies the majority of dentate restructuring. Recently, attention has focused on the mammalian target of rapamycin (mTOR) signaling pathway as a potential mediator of epileptogenic change. Systemic administration of the mTOR inhibitor rapamycin has promising therapeutic potential, as it has been shown to reduce seizure frequency and seizure severity in rodent models. Here, we tested whether mTOR signaling facilitates abnormal development of granule cells during epileptogenesis. We also examined dentate inflammation and mossy cell death in the dentate hilus. To determine if mTOR activation is necessary for abnormal granule cell development, transgenic mice that harbored fluorescently-labeled adult-born granule cells were treated with rapamycin following pilocarpine-induced status epilepticus. Systemic rapamycin effectively blocked phosphorylation of S6 protein (a readout of mTOR activity) and reduced granule cell mossy fiber axon sprouting. However, the accumulation of ectopic granule cells and granule cells with aberrant basal dendrites was not significantly reduced. Mossy cell death and reactive astrocytosis were also unaffected. These data suggest that anti-epileptogenic effects of mTOR inhibition may be mediated by mechanisms other than inhibition of these common dentate pathologies. Consistent with this conclusion, rapamycin prevented pathological weight gain in epileptic mice, suggesting that rapamycin might act on central circuits or even peripheral tissues controlling weight gain in epilepsy.

Keywords: Dentate granule cell; Dentate gyrus; Epilepsy; Epileptogenesis; Hippocampus; Inflammation; Mossy fiber sprouting; Neurogenesis; Obesity; Rapamycin; mTOR.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hippocampus / drug effects
  • Hippocampus / pathology*
  • Immunosuppressive Agents / therapeutic use*
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / pathology
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Neurons / pathology
  • Pilocarpine / toxicity
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sirolimus / therapeutic use*
  • Status Epilepticus / chemically induced
  • Status Epilepticus / complications*
  • Status Epilepticus / pathology
  • Status Epilepticus / therapy*
  • Weight Gain / drug effects*
  • Weight Gain / genetics
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • Carrier Proteins
  • Gli1 protein, mouse
  • Immunosuppressive Agents
  • Membrane Proteins
  • Membrane Transport Proteins
  • Slc30a3 protein, mouse
  • Zinc Finger Protein GLI1
  • Pilocarpine
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Sirolimus