Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

Abstract

Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

Altered Protein Profiles During Epileptogenesis in the Pilocarpine Mouse Model of Temporal Lobe Epilepsy

“…Cell-specific mutations of TSC genes induced in both glia and neurons cause epilepsy in mice (44)(45)(46). Further, the neuropathological hallmarks of TSC include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia, as well as in neurons (47), and abnormal function of the mTOR pathway in glial cells is thought to contribute to seizures as well as cognitive co-morbidities in TSC as well as in TLE (48,49). Specimens surgically removed from people suffering from TLE show increased levels of pMTOR (S2448), pS6 (S235/236), and pS6 (S240/244) that are consistent with the activation of the mTOR pathway.…”

Suppression of Microgliosis With the Colony-Stimulating Factor 1 Receptor Inhibitor PLX3397 Does Not Attenuate Memory Defects During Epileptogenesis in the Rat

“…CSF1R is part of a family of receptors that are responsible for regulating microglial proliferation, survival, motility, and adhesion (14)(15)(16). As opposed to mTOR signaling, which is highly conserved across species and is ubiquitously found in numerous cell types (12), CSF1R is mainly expressed in microglia (14)(15)(16). In fact, mutations in this CSF1R receptor are associated with the loss of microglia and development of epilepsy in humans (17).…”

“…Importantly, we found that inhibition of mTOR signaling with the drug rapamycin during SE-induced epileptogenesis suppressed microgliosis and attenuated the associated memory loss ( 8 ). While this evidence suggests that reactive microglial cells may be active participants underlying cognitive dysfunctions in SE and TLE, mTOR signaling cascade is expressed in neurons and astrocytes ( 12 ), thereby indicating that these other cell types may also play a role in this pathophysiology.…”

Relationship Status Update on Astrocytic VEGFR-3 and mTOR Signaling: It’s Complicated

“… 2 While little is known on the impact that aberrant VEGFR-3 activation has in epilepsy, disruptions in cell-specific roles of mTOR signaling, such as those involved in the regulation of protein synthesis in dendrites, inflammatory/phagocytic properties in microglia, and glutamate transport mechanisms in astrocytes, can promote neuronal instability and hyperexcitability. 3 - 5 Consequently, mTOR hyperactivation has been linked to epileptogenesis and the generation of unprovoked seizures in both preclinical experimental models and drug-resistant epilepsies in humans. 3 - 5 Evidence that VEGFR-3 may be an upstream regulator of mTOR suggests that VEGFR-3/mTOR signaling may play a role in astrocytic-mediated epileptogenic processes.…”

“… 3 - 5 Consequently, mTOR hyperactivation has been linked to epileptogenesis and the generation of unprovoked seizures in both preclinical experimental models and drug-resistant epilepsies in humans. 3 - 5 Evidence that VEGFR-3 may be an upstream regulator of mTOR suggests that VEGFR-3/mTOR signaling may play a role in astrocytic-mediated epileptogenic processes. Thus, the study by Jeong et al interrogated whether VEGFR-3 signaling mediated mTOR activation as well as the dysregulation of glutamate transporter 1 (GLT-1) and reactive astrocytosis following pilocarpine-induced status epilepticus (SE) in mice.…”