Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model

Abstract

Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1+/− mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (<P19). Seizures are generated intracortically in the granular layer of the neocortex. Slow kinetics of aberrant GluN2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in Tsc1+/− mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients.

Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders

“…The pathophysiology of this disorder is still far from clear. For example, although tubers have long been suspected to be the source of epileptic activity and are still removed surgically in TS patients with intractable epilepsy, a number of mouse models of the disorder present with spontaneous seizures, but lack tubers (Goorden et al, 2007; Lozovaya et al, 2014). In addition, recordings in patients suggest tubers are electrically silent, focusing the search for epileptic foci on surrounding tissue (Schwartzkroin and Wenzel, 2012).…”

mTOR Inhibition in Epilepsy: Rationale and Clinical Perspectives

“…The modulation of late phase long-term potentiation and synaptic excitability by rapamycin likely involves direct regulation of synaptic proteins [7,49,51,53]. However, unlike conventional antiseizure medications that typically bind directly to synaptic receptors and channels, rapamycin probably affects neuronal excitability indirectly by regulating the translation and expression of voltage-gated ion channels [49,54,55] or neurotransmitter transporters and receptors [29,56–58]. …”

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

“…[43][44][45] In addition, heterozygous germline missense mutations or haploinsufficiency of TSC1 or TSC2 is sufficient to cause hyperactivation of the mTOR pathway and various symptoms of TSC, including epilepsy. 37,[46][47][48] Therefore, it is likely that the identified somatic mutations induce hyperactivation of the mTOR pathway by affecting the formation or function of the TSC complex.…”