ABSTRACT
BACKGROUND: Alterations in white matter (WM) integrity observed in patients with obsessive-compulsive disorder (OCD) may be at least partly determined genetically. Neuroimaging measures of WM microstructure could serve as promising intermediate phenotypes for genetic analysis of the disorder. The objective of the present study was to explore the association between variability in genes related to the pathophysiology of OCD and altered WM microstructure previously identified in child and adolescent patients with the disease. METHODS: Fractional anisotropy (FA) and mean diffusivity (MD) measured by diffusion tensor imaging (DTI) and 262 single nucleotide polymorphisms (SNPs) in 35 candidate genes were assessed concomitantly in 54 child and adolescent OCD patients. RESULTS: Six polymorphisms located in the glutamate transporter gene (SLC1A1 rs3087879), dopamine transporter gene (SLC6A3 rs4975646), dopamine receptor D3 (DRD3 rs3773679), nerve growth factor receptor gene (NGFR rs734194 and rs2072446), and cadherin 9 gene (CDH9 rs6885387) showed significant p-values after Bonferroni correction (p≤0.00019). More specifically, the vast majority of these associations were detected with MD in the right and left anterior and posterior cerebellar lobes. LIMITATIONS: Patients were under pharmacological treatment at the time of the DTI examination. Sample size is limited. CONCLUSIONS: The results provide the first evidence of the involvement of genetic variants related to glutamatergic, dopaminergic, and neurodevelopmental pathways in determining the WM microstructure of child and adolescent patients with OCD, which could be related to the neurobiology of the disorder.
Subject(s)
Dopaminergic Neurons/physiology , Excitatory Amino Acids/genetics , Genetic Variation , Neural Pathways/physiopathology , Obsessive-Compulsive Disorder/genetics , White Matter/pathology , Adolescent , Anisotropy , Cadherins/genetics , Child , Diffusion Tensor Imaging/methods , Dopamine Plasma Membrane Transport Proteins/genetics , Excitatory Amino Acid Transporter 3/genetics , Female , Glutamic Acid/genetics , Humans , Male , Nerve Tissue Proteins/genetics , Neuroimaging , Obsessive-Compulsive Disorder/physiopathology , Polymorphism, Single Nucleotide , Receptors, Dopamine D3/genetics , Receptors, Nerve Growth Factor/geneticsABSTRACT
Heritability estimates for alcoholism range from 50% to 60%, pointing out the importance of genetic and environmental factors in its etiology. This review highlights recent advances in translational work investigating genetic influences on alcoholism. We focus on genetic research involving corticotropin-releasing factor, glutamatergic, and opioidergic systems. Variation in the CRF1 receptor gene has been shown to moderate stress-induced alcohol drinking (gene-environment interaction) in animals, and this finding was recently extended to humans. Also, the hyperglutamatergic state, first observed during withdrawal from chronic alcohol exposure in animal models, is associated with aversive and dysphoric states in alcoholics. Pharmacogenetic studies of naltrexone efficacy are in the clinical stages, and recent studies confirmed a differential response dependent on the mu-opioid receptor genotype. Such advances will be essential for the effective treatment of alcoholism in the future.
Subject(s)
Alcoholism/genetics , Genetic Predisposition to Disease/genetics , Alcoholism/complications , Alcoholism/drug therapy , Animals , Corticotropin-Releasing Hormone/genetics , Disease Models, Animal , Excitatory Amino Acids/genetics , Humans , Mice , Naltrexone/therapeutic use , Narcotic Antagonists/therapeutic use , Rats , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Opioid, mu/genetics , Social Environment , Stress, Psychological/complications , Stress, Psychological/geneticsABSTRACT
In the present study, the susceptibility of knockout interleukin-6 (IL-6(-/-)) mice to various convulsant stimuli has been evaluated and compared with other three related mice strains. Animals were treated with chemical convulsants impairing the gamma-aminobutyric acid neurotransmission [pentylenetetrazole (PTZ), picrotoxin, bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), methyl-beta-carboline-3-carboxylate (beta-CCM)], enhancing glutamatergic neurotransmission [N-methyl-d-aspartate (NMDA), alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid (KA)] or a K(+)channel blocker [4-aminopyridine (4-AP)]. The behavioural changes of such convulsant stimuli on IL-6(-/-) were observed and compared with those observed in C57, IL-6(+/+) and DBA/2 mice. The occurrence of clonic and/or tonic seizures was scored and statistically analysed to observe possible differences on seizure susceptibility. The IL-6(-/-) mice exhibited significantly higher seizure susceptibility to PTZ, beta-CCM, DMCM, NMDA, AMPA and KA than did the other mice strains, with the exception of DBA/2 mice. This study demonstrates that IL-6(-/-) mice possess an increased susceptibility to some convulsant stimuli. In particular, the major convulsant effects produced by NMDA, AMPA and KA suggest that the excitatory amino acid system is more active in the central nervous system (CNS) of IL-6(-/-) mice. The present data suggest that IL-6(-/-) mice might be a valid novel epileptic model for the study of pathophysiology and pharmacology of epileptic seizures.
Subject(s)
Convulsants/toxicity , Interleukin-6/deficiency , Interleukin-6/genetics , Seizures/chemically induced , Animals , Disease Susceptibility/immunology , Excitatory Amino Acids/genetics , Excitatory Amino Acids/metabolism , Female , Genetic Predisposition to Disease , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Seizures/genetics , Seizures/metabolismABSTRACT
The full-length cDNA of an excitatory insect selective neurotoxin was amplified from total cDNAs of venomous glands of the scorpion Buthus martensi Karsch (BmK) using the 3'RACE and 5'RACE (rapid amplification of cDNA ends, RACE) method and sequenced. The cDNA encoded a precursor of the insect toxin of 88 amino acid residues, including a signal peptide of 18 residues and a mature toxin of 70 residues. The cDNA deduced sequence of this toxin was homologous with the determined amino acid sequence of BmK IT1, an excitatory insect toxin purified from the scorpion venom, except for three different residues, two at the positions 24-25, and another in the COOH-terminus of the toxin. Among them the COO-terminal residue Gly in the cDNA deduced sequence was predominantly different from the conserved residue Asn found in other known scorpion excitatory insect toxins.
