Inhibition of the Mammalian Target of Rapamycin Signaling Pathway Suppresses Dentate Granule Cell Axon Sprouting in a Rodent Model of Temporal Lobe Epilepsy

Abstract

Dentate granule cell axon (mossy fiber) sprouting is a common abnormality in patients with temporal lobe epilepsy. Mossy fiber sprouting creates an aberrant positive-feedback network among granule cells that does not normally exist. Its role in epileptogenesis is unclear and controversial. If it were possible to block mossy fiber sprouting from developing after epileptogenic treatments, its potential role in the pathogenesis of epilepsy could be tested. Previous attempts to block mossy fiber sprouting have been unsuccessful. The present study targeted the mammalian target of rapamycin (mTOR) signaling pathway, which regulates cell growth and is blocked by rapamycin. Rapamycin was focally, continuously, and unilaterally infused into the dorsal hippocampus for prolonged periods beginning within hours after rats sustained pilocarpine-induced status epilepticus. Infusion for 1 month reduced aberrant Timm staining (a marker of mossy fibers) in the granule cell layer and molecular layer. Infusion for 2 months inhibited mossy fiber sprouting more. However, after rapamycin infusion ceased, aberrant Timm staining developed and approached untreated levels. When onset of infusion began after mossy fiber sprouting had developed for 2 months, rapamycin did not reverse aberrant Timm staining. These findings suggest that inhibition of the mTOR signaling pathway suppressed development of mossy fiber sprouting. However, suppression required continual treatment, and rapamycin treatment did not reverse already established axon reorganization.

Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

“…When the mTOR inhibitor rapamycin, which is clinically used as an immunosuppressant, was administered after termination of SE, it blocked the chronic phase of mTOR activation and reduced mossy-fiber sprouting and the frequency of spontaneous seizures but not neurogenesis or neuronal death (Zeng et al, 2009). Suppression of SE-induced mossy-fiber sprouting by rapamycin has also been reported in the pilocarpine model of TLE (Buckmaster et al, 2009). However, suppression required continual treatment, and rapamycin treatment did not reverse already established axon reorganization (Buckmaster et al, 2009).…”

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

“…Early results with the mTOR inhibitor rapamycin suggested that treatment with this immunosuppressant was disease-modifying in two different models of SE-induced epilepsy [18,19]. Furthermore, Zeng et al [20] found that rapamycin exerted an anti-seizure effect in a mouse model of tuberous sclerosis-a disease in which there is strong evidence supporting a role for the hyperactivation of the mTOR pathway in the pathology of tuberous sclerosis.…”

Deconvoluting mTOR biology

“…[17][18][19][20][21] In other conditions, abnormal mTOR signaling has been implicated in the genesis of recurrent seizures, where it controls mossy fiber sprouting in the hippocampus. [22][23][24] Finally, recent studies have suggested that deregulated mTOR activation might underlie autistic-like behaviors in rodents. 25 Together, these observations highlight the essential role of mTOR in maintaining nervous system homeostasis both in health and in disease.…”