Rapamycin Reverses Status Epilepticus-Induced Memory Deficits and Dendritic Damage

Abstract

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.

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

“…Rapamycin has been shown to inhibit immune responses in normal animals (Lu et al, 2015) and can attenuate epilepsy-associated inflammation (Brewster et al, 2013; Nguyen et al, 2015; Shima et al, 2015), leading us to ask whether rapamycin affected the activation state of astrocytes following SE. Astrocytic activation was first assessed by measuring the soma area of astrocytes in the dentate hilus.…”

“…Negative findings have also been reported (Buckmaster and Lew, 2011; Heng et al, 2013; Sliwa et al, 2012). In addition to improving seizure outcome, animal studies have demonstrated that rapamycin improves cognitive and memory deficits following SE (Brewster et al, 2013). The mechanisms by which rapamycin produces these positive effects, however, are unclear.…”

“…Moreover, rapamycin has robust anti-inflammatory properties (Soliman, 2013). It prevents reactive gliosis following a variety of injuries (Carson et al, 2012; Goldshmit et al, 2015; Li et al, 2015), including seizures (Brewster et al, 2013; Nguyen et al, 2015; Shima et al, 2015). Finally, rapamycin has long been used clinically as an immune suppressant following organ transplants (Geissler and Schlitt, 2010).…”

Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC)

“…Pharmacological antagonism of N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors that lies upstream of mTOR activation, promotes the synthesis of the voltage-gated potassium channel, Kv1.1, in dendrites (34,35). Consistent with these results, in models of temporal lobe epilepsy there is a reduction in the expression of voltage-gated ion channels including Kv1.1 (30,31,36). Interestingly in a model of focal neocortical epilepsy, overexpression of Kv1.1 blocked seizure activity (37).…”

mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development

“…Enhanced mTOR signaling in neurons is associated with alterations in dendritic morphology, changes in dendritic spine density and structure, and diminished long-term depression, all of which can be linked to enhanced excitability and diminished seizure threshold (for comprehensive review, see Lasarge and Danzer 2014). mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with status epilepticus (Brewster et al 2013). Interestingly, the evolution of seizures and autistic behaviors following neonatal brain injury may be mTOR dependent (Talos et al 2012).…”