ABSTRACT
OBJECTIVE: Autism appears to have a strong genetic component. The product of the NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene is included in the mitochondrial electron transport chain. METHOD: We performed a case-control study of 235 patients with autism and 214 controls and examined three single-nucleotide polymorphisms (SNPs) within this gene in a Japanese population. We then conducted a transmission disequilibrium test (TDT) analysis in 148 autistic trios. RESULTS: In the case-control study, two SNPs (rs12666974 and rs3779262) showed a significant association with autism (P=0.00064 and 0.00046 respectively). Furthermore, a haplotype containing these two SNPs showed a significant association (P-global=0.0013, individual haplotype A-A: P=0.010). In TDT analysis, the global and A-A haplotype P-values also indicated significant associations. Minor allele and genotype frequencies were decreased in the autistic subjects. CONCLUSION: We found significant association between the NDFA5 gene and autism.
Subject(s)
Autistic Disorder/genetics , NADH Dehydrogenase/genetics , Polymorphism, Single Nucleotide/genetics , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Female , Genetic Association Studies , Genetic Linkage/genetics , Genotype , Haplotypes/genetics , Humans , Male , Young AdultABSTRACT
The anti-convulsive effects of neuropeptide Y have been suggested in several animal models of epilepsy. We have found the sustained increase of neuropeptide Y contents and the seizure-induced elevation of hippocampal messenger RNA in a novel spontaneous epileptic mutant rat: Noda epileptic rat. In the present study, we investigated the change of neuropeptide Y Y1 and Y2 receptor messenger RNA expressions and binding sites in the hippocampus following a spontaneous generalized tonic-clonic seizure of Noda epileptic rat. Furthermore, the binding sites of a more recently isolated receptor subtype, neuropeptide Y Y5 receptors, were also evaluated by receptor autoradiography. A marked elevation of neuropeptide Y immunoreactivity in the mossy fiber, and Y2-receptor up-regulation in the dentate gyrus were observed in the hippocampus of Noda epileptic rat, which coincided with the previous results of the other epileptic models. In contrast, Y1-receptor down-regulation was not found after a spontaneous seizure of Noda epileptic rat while this occurs in kindling and after kainic acid-induced seizures. [125I][Leu31, Pro34]peptide YY/BIBP 3226-insensitive (Y5 receptor) binding sites in CA1 stratum radiatum were significantly decreased following a spontaneous seizure of Noda epileptic rat. The present results suggest that a spontaneous seizure of Noda epileptic rat induces significant changes in neuropeptide Y-mediated transmission in the hippocampus via Y2 and Y5 receptors, but not Y1 receptors. Therefore, specific subset of neuropeptide Y receptor subtypes might be involved in the epileptogenesis of Noda epileptic rat.
Subject(s)
Epilepsy/genetics , Hippocampus/metabolism , Neurons/metabolism , Neuropeptide Y/metabolism , Receptors, Neuropeptide Y/genetics , Animals , Dentate Gyrus/cytology , Dentate Gyrus/metabolism , Dentate Gyrus/physiopathology , Disease Models, Animal , Epilepsy/metabolism , Epilepsy/physiopathology , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Hippocampus/cytology , Hippocampus/physiopathology , Immunohistochemistry , Iodine Radioisotopes , Male , Mossy Fibers, Hippocampal/metabolism , Mossy Fibers, Hippocampal/physiopathology , Mossy Fibers, Hippocampal/ultrastructure , Neurons/cytology , Neurons/drug effects , Peptide Fragments/pharmacology , Pyramidal Cells/cytology , Pyramidal Cells/metabolism , RNA, Messenger/metabolism , Rats , Rats, Mutant StrainsABSTRACT
Noda epileptic rat (NER) is a new epileptic rat strain, which was developed by inbreeding rats with spontaneous tonic-clonic seizures in a stock of Crj:Wistar. In the present study, possible changes of two neuropeptides, neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), in the brains of NER were investigated. Increased contents of immunoreactive (IR) NPY were found in the striatum and amygdala of 8-week NERs with partial seizure, while these changes extended to the limbic region including hippocampus in 16-week NERs with fully developed generalized tonic-clonic seizure. IR-CRF were elevated only in the entorhinal and pyriform cortex of both 8-week and 16-week NERs. Generalized tonic-clonic seizure in NERs induced a transient increase of NPY mRNA in the granular layer of dentate gyrus. These results suggest that NPY metabolism in the limbic brain contributes to the seizure susceptibility in this model of epilepsy.