Abstract
Mammalian target of rapamycin (mTOR) is a protein kinase that senses nutrient availability, trophic factors support, cellular energy level, cellular stress, and neurotransmitters and adjusts cellular metabolism accordingly. Adequate mTOR activity is needed for development as well as proper physiology of mature neurons. Consequently, changes in mTOR activity are often observed in neuropathology. Recently, several groups reported that seizures increase mammalian target of rapamycin (mTOR) kinase activity, and such increased activity in genetic models can contribute to spontaneous seizures. However, the current knowledge about the spatiotemporal pattern of mTOR activation induced by proconvulsive agents is rather rudimentary. Also consequences of insufficient mTOR activity on a status epilepticus are poorly understood. Here, we systematically investigated these two issues. We showed that mTOR signaling was activated by kainic acid (KA)-induced status epilepticus through several brain areas, including the hippocampus and cortex as well as revealed two waves of mTOR activation: an early wave (2 h) that occurs in neurons and a late wave that predominantly occurs in astrocytes. Unexpectedly, we found that pretreatment with rapamycin, a potent mTOR inhibitor, gradually (i) sensitized animals to KA treatment and (ii) induced gross anatomical changes in the brain.
Highlights
Mammalian target of rapamycin is a protein kinase that senses nutrient availability, trophic factors, cellular energy level, and cellular stress and adjusts cellular metabolism [1]
We showed that kainic acid (KA) treatment activated Mammalian target of rapamycin (mTOR) signaling in several brain areas
With regard to the second aim, we showed that chronic systemic rapamycin treatment, which inhibited mTOR signaling in hippocampi and cortex gradually led to facilitation of KA-induced status epilepticus and epileptic discharges as well as induced gross morphological changes in the brain
Summary
Mammalian target of rapamycin (mTOR) is a protein kinase that senses nutrient availability, trophic factors, cellular energy level, and cellular stress and adjusts cellular metabolism [1]. MTOR plays several roles in neuronal development and plasticity [3,4,5]. MTOR activity is controlled by neurotransmitters [2]. It is involved in the control of neuronal survival [6,7], neurite growth [8,9,10], and synapse formation [9]. In several animal models of epileptogenesis (e.g., kainic acid [KA]- or pilocarpine-induced status epilepticus), increased mTOR activity was biochemically proven [16,17,18]. Zeng et al [17] and Buckamster et al [18] found that the prolonged administration of rapamycin suppressed mossy fiber sprouting
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