RRC ID 33275
Author Ohmori I, Kawakami N, Liu S, Wang H, Miyazaki I, Asanuma M, Michiue H, Matsui H, Mashimo T, Ouchida M.
Title Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation.
Journal Epilepsia
Abstract OBJECTIVE:Developmental disorders including cognitive deficit, hyperkinetic disorder, and autistic behaviors are frequently comorbid in epileptic patients with SCN1A mutations. However, the mechanisms underlying these developmental disorders are poorly understood and treatments are currently unavailable. Using a rodent model with an Scn1a mutation, we aimed to elucidate the pathophysiologic basis and potential therapeutic treatments for developmental disorders stemming from Scn1a mutations.
METHODS:We conducted behavioral analyses on rats with the N1417H-Scn1a mutation. With high-performance liquid chromatography, we measured dopamine and its metabolites in the frontal cortex, striatum, nucleus accumbens, and midbrain. Methylphenidate was administered intraperitoneally to examine its effects on developmental disorder-like behaviors and hyperthermia-induced seizures.
RESULTS:Behavioral studies revealed that Scn1a-mutant rats had repetitive behavior, hyperactivity, anxiety-like behavior, spatial learning impairments, and motor imbalance. Dopamine levels in the striatum and nucleus accumbens in Scn1a-mutant rats were significantly lower than those in wild-type rats. In Scn1a-mutant rats, methylphenidate, by increasing dopamine levels in the synaptic cleft, improved hyperactivity, anxiety-like behavior, and spatial learning impairments. Surprisingly, methylphenidate also strongly suppressed hyperthermia-induced seizures.
SIGNIFICANCE:Dysfunction of the mesolimbic dopamine reward pathway may contribute to the hyperactivity and learning impairments in Scn1a-mutant rats. Methylphenidate was effective for treating hyperactivity, learning impairments, and hyperthermia-induced seizures. We propose that methylphenidate treatment may ameliorate not only developmental disorders but also epileptic seizures in patients with SCN1A mutations.
Volume 55(10)
Pages 1558-67
Published 2014-10
DOI 10.1111/epi.12750
PMID 25154505
MeSH Animals Behavior, Animal / drug effects Central Nervous System Stimulants / therapeutic use* Corpus Striatum / chemistry Dopamine / analysis Fever / complications* Hyperkinesis / drug therapy Hyperkinesis / genetics Learning / drug effects* Male Methylphenidate / therapeutic use* Mutation, Missense / genetics NAV1.1 Voltage-Gated Sodium Channel / genetics* Nucleus Accumbens / chemistry Rats Rats, Mutant Strains Seizures / drug therapy* Seizures / etiology Seizures / genetics Stereotyped Behavior / drug effects
IF 5.562
Times Cited 9
Rats F344-Scn1am1Kyo (strainID=716)