Abnormal increased mTOR signaling regulates seizure threshold in Dravet syndrome.

ABSTRACT

Excessive activation of mTOR has been observed in the brains of mouse models for Dravet syndrome. We aim to confirm whether that the overactivation of mTOR contributes to the neuropathological changes leading to epileptogenesis and neurobehavior deficits to support a novel pharmacological therapeutic approach for Dravet syndrome. The mTOR inhibitor everolimus, as a clinical antiseizure medication, was utilized to investigate whether mTOR is involved in hyperthermia-induced seizures, anxiety-like, and autism-like behaviors, as well as to explore potential pathogenic mechanisms in Scn1aE1099X/+ mice, a model of Dravet syndrome. First, we found that mTOR signaling was upregulated in hippocampus tissues and neural cultures derived from Scn1aE1099X/+ mice prior to seizure onset. Behaviorally, everolimus increased the seizure threshold and improved anxiety-like and autism-like behaviors in Scn1aE1099X/+ mice. Electrophysiologically, everolimus reduced the frequency of spontaneous excitatory postsynaptic currents in dentate granule neurons from Scn1aE1099X/+ mice. Biochemically, everolimus prevented hyperthermia-induced phosphorylation of hippocampal S6 ribosome in hippocampus, and it delayed hyperthermia-induced increase of cytosolic Ca2+ level in primary neuronal cultures derived from Scn1aE1099X/+ mice. Our results provide the evidence that overactivated mTOR as an important neuropathological change which regulates seizure threshold, impairments of neurobehavior, neuronal glutamatergic transmission and intracellular Ca2+ levels in Scn1aE1099X/+ mice. Inhibition of mTOR is a potential pharmacological therapeutic approach.