mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy

Abstract

Several signaling pathways are believed to be involved in the epileptogenic process that triggers the subsequent changes in the brain causing epilepsy. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that in the brain, regulates several important physiological functions such as neuronal development and synaptic plasticity, and also seems to be involved in many pathologies, including epilepsy and psychiatric disorders. Previous work in animal models of both genetic and acquired generalized convulsive epilepsies, has suggested that modulators of the mTOR signaling pathway may have beneficial neuroprotective and antiepileptogenic effects. Here, we investigated for the first time, the effect of some treatment schedules (i.e. early chronic, sub-chronic and acute) with the specific mTOR inhibitor rapamycin, on the development of absence seizures and seizure parameters as well as depressive-like behavior in WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity. In addition, we studied the possible interaction between rapamycin treatment and the effects of bacterial lipopolysaccharide (LPS) endotoxin administration, which is known to aggravate absence seizures through generation of increased neuroinflammatory responses. We found that rapamycin (early chronic treatment for 17 weeks, starting at P45) exhibited clear antiepileptogenic properties also in this animal epilepsy model; however, this effect was accompanied by unexpected prodepressant effects. Both acute and sub-chronic (7 day) treatments also had anti-absence properties, but the sub-chronic treatment produced contrasting antidepressant properties in the WAG/Rij rats that were not seen in control Wistar rats. The rapamycin/LPS co-administration studies showed that rapamycin blocked or prevented the LPS-dependent increase in absence seizures, suggesting an anti-inflammatory-like protective action. In conclusion, we have demonstrated a novel antiepileptogenic effect of rapamycin in a well-established animal model of absence epilepsy, and we suggest that this effect may be mediated by the inhibition of inflammatory processes that are developed in the brain of these specific animals during epileptogenesis and during seizures. Our experiments here suggest new insights into this intriguing field, which deserves to be further explored. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'.