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

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.

Mechanistic target of rapamycin complex 1 and 2 in human temporal lobe epilepsy

“…Noteworthy, rapamycin can also suppress the sprouting of inhibitory hilar neurons axons, which may possibly have negative net effects on hippocampal hyperexcitability. 59 Besides inhibiting mossy fiber sprouting, rapamycin has little or no effect on other SE-induced GCL phenotypes, including basal dendrite formation and ectopic granule cell generation, 57,60,61 which may explain the negative results on seizure prevention in some models. 57,60 Another potential mechanism by which increased activation of mTORC1 within the temporal lobe structures may promote epileptogenesis is by altering expression and function of neurotransmitter receptors and ion channels, given that previous studies have demonstrated that rapamycin treatment prevented seizure-induced enhancement of glutamatergic function 4 and reversed several ion channels abnormalities in hippocampal neurons.…”

Disrupted female estrous cyclicity in the intrahippocampal kainic acid mouse model of temporal lobe epilepsy

“…Increased weight gain has been observed in the systemic pilocarpine mouse and rat models of TLE. 12,26 In one study examining the intrahippocampal KA female rat model, increased food intake and body weight gain were observed only when both ventral and dorsal hippocampus was injected. 27 In our study, the KA was injected only to the right dorsal hippocampus of the mice.…”

Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells

“…basal dendrites, Pun et al, 2012). Moreover, mTOR signaling is increased during epileptogenesis (Hester et al, 2016; Zeng et al, 2009), and blocking mTOR has anti-epileptogenic properties (Ljungberg et al, 2009; Wong, 2013). PTEN knockout mice developed a severe epilepsy syndrome, exhibiting both hippocampal and cortical seizures in 24/7 EEG recordings -- supporting the hypothesis that abnormal granule cells can initiate temporal lobe epileptogenesis.…”