ABSTRACT
STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.
Subject(s)
Corpus Striatum/metabolism , Munc18 Proteins/genetics , NAV1.2 Voltage-Gated Sodium Channel/genetics , Neocortex/metabolism , Seizures/genetics , Synaptic Transmission , Action Potentials/drug effects , Animals , Anticonvulsants/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/pathology , Dioxoles/pharmacology , Electroencephalography , Epilepsy, Absence/drug therapy , Epilepsy, Absence/genetics , Epilepsy, Absence/metabolism , Epilepsy, Absence/physiopathology , Ethosuximide/pharmacology , Gene Expression Regulation , Haploinsufficiency , Interneurons/drug effects , Interneurons/metabolism , Interneurons/pathology , Mice , Mice, Knockout , Munc18 Proteins/deficiency , NAV1.2 Voltage-Gated Sodium Channel/deficiency , Neocortex/drug effects , Neocortex/pathology , Neural Pathways/drug effects , Neural Pathways/metabolism , Piperidines/pharmacology , Receptors, AMPA/genetics , Receptors, AMPA/metabolism , Seizures/metabolism , Seizures/physiopathology , Seizures/prevention & control , Signal Transduction , Thalamus/drug effects , Thalamus/metabolismABSTRACT
PURPOSE: We previously reported a mutant mouse carrying a severe myoclonic epilepsy in infancy (SMEI) mutation in Scn1a. In this study, we examined the susceptibility to hyperthermia-induced seizures of heterozygous Scn1a mutant mice (Scn1a(RX/+)) and wild-type (Scn1a(+/+) ) mice. Then we assessed the efficacy of stiripentol (STP) monotherapy versus STP and clobazam (CLB) combination therapy to prevent hyperthermia-induced seizures in Scn1a(RX/+) mice. METHODS: The seizure-inducing body temperatures in Scn1a(RX/+) mice and age-matched Scn1a(+/+) mice were compared in three age groups (1 month, 3-5 months, > 6 months). Then STP, CLB, or STP + CLB was administered intraperitoneally to Scn1a(RX/+) mice of two age groups (p1M, aged 1 month; p5M, aged 5-10 months). The efficacy of medications was assessed by comparing the seizure-inducing body temperature and the duration of seizures. KEY FINDINGS: The seizure-inducing body temperature was significantly lower in Scn1a(RX/+) than in Scn1a(+/+) mice for all age groups (p < 0.01). The seizure-inducing body temperature was significantly elevated after administration of STP in p1M (p < 0.05) but not in p5M (p > 0.05), and it was significantly elevated after administration of CLB in both age groups (p < 0.05). The seizure-inducing body temperature was significantly higher after administration of STP + CLB than after administration of CLB in p5M (p < 0.05). SIGNIFICANCE: Scn1a (RX/+) mice have increased susceptibility to hyperthermia-induced seizure in all age groups. STP monotherapy is effective in preventing hyperthermia-induced seizures in Scn1a(RX/+) mice aged 1 month, but not in those aged 5 months and older. When used in combination therapy with CLB, STP inhibits the metabolism of CLB and probably synergistically enhances the anticonvulsant effect in mice aged 1 month.