Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio‐temporal lobe epilepsy

Abstract

Recent studies in animal models have suggested that the mammalian target of rapamycin (mTOR) signaling pathway is involved in several features of mesio-temporal lobe epilepsy (MTLE), and that its inhibition could have therapeutic interests. However, it remains controversial whether mTOR activation is the cause or the consequence of MTLE. We previously showed in a mouse model of MTLE associated with hippocampal sclerosis that increased neuronal excitability and brain-derived neurotrophic factor (BDNF) overexpression contribute to the development of morphological features of this form of epilepsy. Here, we addressed whether mTOR activation promotes MTLE epileptogenesis via increasing neuronal excitability and/or BDNF expression or rather mediates neuroplasticity associated with hippocampal sclerosis. In mice injected intrahippocampally with kainate (1 nmol), we showed a biphasic increase of phospho-S6 (p-S6) ribosomal protein expression, the downstream product of the mTOR signaling pathway, in the dispersed granule cell layer (GCL) of the dentate gyrus with a second phase lasting up to 6 months. Chronic treatment with rapamycin suppressed p-S6 expression, granule cell dispersion and mossy fiber sprouting, but did not reduce cell loss, BDNF overexpression, glutamic acid decarboxylase (GAD)67 expression or the development of hippocampal paroxysmal discharges. Neuronal inhibition by midazolam (2 × 10 mg/kg, i.p.) abolished the increased expression of p-S6 in the dispersed GCL. Our data suggest that activation of the mTOR signaling pathway results from the increased neuronal excitation that develops in the GCL and may contribute to MTLE morphological changes. However, these data do not support the role of this pathway in the development of MTLE or its inhibition as a therapy for this form of epilepsy.

Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats

“…26 It is not yet understood through what mechanisms mTOR inhibition could suppress or modify seizures. Although some studies argue that mTOR activation is merely secondary to increased neuronal excitability and seizures rather than contributing to it, 27,28 it is known that mTOR inhibition can reduce a number of pro-epileptogenic processes such as hilar cell loss, formation of ectopic granule cells, and most evidently, mossy fiber sprouting. 9,12,29,30 Because mossy fiber sprouting is associated with seizure development after SE, one could hypothesize that rapamycin exerts its effects (at least in part) through inhibition of mossy fiber sprouting.…”

Effects of eugenol on granule cell dispersion in a mouse model of temporal lobe epilepsy

“…To clarify whether mTORC1 deactivation affected GCD following KA-induced seizures, we further examined the effect of RA, a specific inhibitor of mTORC1, on the GCD in the KA-treated hippocampus (Shima et al, 2015). Our Nissl staining results revealed that KA-induced GCD was decreased in the DG of RA-treated mice (Fig.…”

“…S1). Rapamycin [RA; 10 mg/kg (Jeon et al, 2015); LC Laboratories, Woburn, MA, USA], which was diluted in a vehicle solution (4% ethanol, 5% Tween 80, and 5% PEG 400; Sigma), was used as a positive control for GCD changes mediated by mTORC1 deactivation (Shima et al, 2015).…”

“…For Nissl staining, sections were mounted on gelatin-coated slides and stained with 0.5% cresyl violet (Sigma). The presence of GCD was determined by measuring the average width of the GCL in the mid and medial one-fourth portions of the upper blade of the DG (Shima et al, 2015). GCD was expressed as a percentage of the GCL width on the ipsilateral side compared with that on the contralateral side.…”

“…In a mouse model of TLE and in patients with sclerotic hippocampus, the mammalian target of rapamycin (mTOR) signaling pathway was hyperactivated in dispersed granule cells, indicating that mTORC1 activity is involved in GCD induced by epileptic insults (Sha et al, 2012;Shima et al, 2015). In addition, mTOR deactivation due to RA treatment significantly reduces spontaneous recurrent seizures (Huang et al, 2010;Zeng et al, 2009).…”