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  • 1
    Language: English
    In: PLoS ONE, 2011, Vol.6(8), p.e23373
    Description: Genome-wide association studies implicate variations in CHRNA5 and CHRNA3 as being associated with nicotine addiction (NA). Multiple common haplotypes (“risk”, “mixed” and “protective”) exist in Europeans; however, high linkage disequilibrium between variations in CHRNA5 and CHRNA3 makes assigning causative allele(s) for NA difficult through genotyping experiments alone. We investigated whether CHRNA5 or CHRNA3 promoter haplotypes, associated previously with NA, might influence allelic expression levels. For in vitro analyses, promoter haplotypes were sub-cloned into a luciferase reporter vector. When assessed in BE(2)-C cells, luciferase expression was equivalent among CHRNA3 haplotypes, but the combination of deletion at rs3841324 and variation at rs503464 decreased CHRNA5 promoter-derived luciferase activity, possibly due to loss of an SP-1 and other site(s). Variation within the CHRNA5 5’UTR at rs55853698 and rs55781567 also altered luciferase expression in BE(2)-C cells. Allelic expression imbalance (AEI) from the “risk” or “protective” haplotypes was assessed in post-mortem brain tissue from individuals heterozygous at coding polymorphisms in CHRNA3 (rs1051730) or CHRNA5 (rs16969968). In most cases, equivalent allelic expression was observed; however, one individual showed CHRNA5 AEI that favored the “protective” allele and that was concordant with heterozygosity at polymorphisms ∼13.5 kb upstream of the CHRNA5 transcription start site. Putative enhancer activity from these distal promoter elements was assessed using heterologous promoter constructs. We observed no differences in promoter activity from the two distal promoter haplotypes examined, but found that the distal promoter region strongly repressed transcription. We conclude that CHRNA5 promoter variants may affect relative risk for NA in some heterozygous individuals.
    Subject(s): Research Article ; Biology ; Genetics And Genomics ; Neuroscience
    E-ISSN: 1932-6203
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  • 2
    In: Epilepsia, December 2010, Vol.51, pp.58-58
    Description: Most human epilepsies are multifactorial, resulting from combined effects of genes and environment. The large number of genes whose variation and/or mutation influences the development and progression of epilepsy are only now beginning to be identified. Advanced methods of genetic analysis promise to facilitate understanding of pathogenesis and establishment of new effective treatments. For an expanded treatment of this topic see (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at ).
    Subject(s): Association Studies ; Copy Number Variations ; Dna Sequencing ; Genome‐Wide Association ; Linkage Analysis ; Seizures ; Single Nucleotide Polymorphism Snp ; Susceptibility Loci
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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  • 3
    In: Epilepsia, September 2010, Vol.51(9), pp.1882-1885
    Description: We performed a meta‐analysis to evaluate the association between polymorphisms and the prevalence of epilepsy, including all relevant human studies (until June 2009), in which patients with or without epilepsy had undergone genotyping for the gene. Odds ratios (ORs) were calculated using a random effects model. We identified 9 case–control studies that included a total of 3,996 patients (2,454 with epilepsy and 1,542 nonepileptic subjects). No association was found between polymorphisms and the risk of having epilepsy (odds ratio 1.07, 95% confidence interval 0.76–1.51; p = 0.34). genotyping for epileptic patients is not warranted.
    Subject(s): Mdr1 ; Abcb1 C3435t ; Epilepsy ; Polymorphism ; Meta‐Analysis
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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  • 4
    In: Epilepsia, August 2012, Vol.53(8), pp.1429-1435
    Description: Most common forms of human epilepsy result from a complex combination of polygenetic and environmental factors. Quantitative trait locus (QTL) mapping is a first step toward the nonbiased discovery of epilepsy‐related candidate genes. QTL studies of susceptibility to induced seizures in mouse strains have consistently converged on a distal region of chromosome 1 as a major phenotypic determinant; however, its influence on spontaneous epilepsy remains unclear. In the present study we characterized the influence of allelic variations within this QTL, termed , on the occurrence of spontaneous spike‐wave discharges (SWDs) characteristic of absence seizures in DBA/2 (D2) mice. We analyzed SWD occurrence and patterns in freely behaving D2, C57BL/6 (B6) and the congenic strains D2.B6‐ and B6.D2‐. We showed that congenic manipulation of the locus drastically reduced the number and the duration of SWDs in D2.B6‐ mice, which are homozygous for from B6 strain on a D2 strain background. However, it failed to induce the full expression of SWDs in the reverse congenic animals B6.D2‐. Our results demonstrate that the occurrence of SWDs in D2 animals is under polygenic control and, therefore, the D2 and B6 strains might be a useful model to dissect the genetic determinants of polygenic SWDs characteristic of typical absence seizures. Furthermore, we point to the existence of epistatic interactions between at least one modifier gene within and genes within unlinked QTLs in regulating the occurrence of spontaneous nonconvulsive forms of epilepsies.
    Subject(s): Epilepsy ; Spike‐Wave Discharges ; Eeg ; Quantitative Trait Loci ; Congenic Mice
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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  • 5
    In: Epilepsia, September 2010, Vol.51(9), pp.1707-1713
    Description: encodes subunits of inward rectifying potassium (Kir) channel Kir4.1 found predominantly in glial cells within the brain. Genetic inactivation of these channels in glia impairs extracellular K and glutamate clearance and produces a seizure phenotype. In both mice and humans, polymorphisms and mutations in the gene have been associated with seizure susceptibility. The purpose of the present study was to determine whether there are differences in Kir channel activity and potassium‐ and glutamate‐buffering capabilities between astrocytes from seizure resistant C57BL/6 (B6) and seizure susceptible DBA/2 (D2) mice that are consistent with an altered K channel activity as a result of genetic polymorphism of . Using cultured astrocytes and hippocampal brain slices together with whole‐cell patch‐clamp, we determined the electrophysiologic properties, particularly K conductances, of B6 and D2 mouse astrocytes. Using a colorimetric assay, we determined glutamate clearance capacity by B6 and D2 astrocytes. Barium‐sensitive Kir currents elicited from B6 astrocytes are substantially larger than those elicited from D2 astrocytes. In addition, potassium and glutamate buffering by D2 cortical astrocytes is impaired, relative to buffering by B6 astrocytes. In summary, the activity of Kir4.1 channels differs between seizure‐susceptible D2 and seizure‐resistant B6 mice. Reduced activity of Kir4.1 channels in astrocytes of D2 mice is associated with deficits in potassium and glutamate buffering. These deficits may, in part, explain the relatively low seizure threshold of D2 mice.
    Subject(s): Astrocyte ; Seizure ; Potassium Buffering ; Glutamate Clearance ; Kir4.1
    ISSN: 0013-9580
    E-ISSN: 1528-1167
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  • 6
    Language: English
    In: Alzheimer's & dementia, July 2015, Vol.11(7), pp.P500-P500
    ISSN: 1552-5260
    E-ISSN: 1552-5279
    Source: ScienceDirect Journals (Elsevier)
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  • 7
    Language: English
    In: BMC genomics, 03 October 2013, Vol.14, pp.678
    Description: Blood-brain barrier (BBB) disruption is an integral feature of numerous neurological disorders. However, there is a relative lack of knowledge regarding the underlying molecular mechanisms of immune-mediated BBB disruption. We have previously shown that CD8 T cells and perforin play critical roles in initiating altered permeability of the BBB in the peptide-induced fatal syndrome (PIFS) model developed by our laboratory. Additionally, despite having indistinguishable CD8 T cell responses, C57BL/6J (B6) mice are highly susceptible to PIFS, exhibiting functional motor deficits, increased astrocyte activation, and severe CNS vascular permeability, while 129S1/SvImJ (129S1) mice remain resistant. Therefore, to investigate the potential role of genetic factors, we performed a comprehensive genetic analysis of (B6 x 129S1) F2 progeny to define quantitative trait loci (QTL) linked to the phenotypic characteristics stated above that mediate CD8 T cell-initiated BBB disruption. Using single nucleotide polymorphism (SNP) markers and a 95% confidence interval, we identified one QTL (PIFS1) on chromosome 12 linked to deficits in motor function (SNP markers rs6292954, rs13481303, rs3655057, and rs13481324, LOD score = 3.3). In addition we identified a second QTL (PIFS2) on chromosome 17 linked to changes in CNS vascular permeability (SNP markers rs6196216 and rs3672065, LOD score = 3.7). The QTL critical intervals discovered have allowed for compilation of a list of candidate genes implicated in regulating functional deficit and CNS vascular permeability. These genes encode for factors that may be potential targets for therapeutic approaches to treat disorders characterized by CD8 T cell-mediated BBB disruption.
    Subject(s): Genetic Association Studies ; Blood-Brain Barrier -- Pathology ; Cd8-Positive T-Lymphocytes -- Immunology ; Capillary Permeability -- Genetics ; Quantitative Trait Loci -- Genetics
    ISSN: 1471-2164
    E-ISSN: 1471-2164
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  • 8
    Language: English
    In: Frontiers in systems neuroscience, 01 June 2014, Vol.8
    Description: The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14h/10h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence...
    Subject(s): Arntl Transcription Factors ; Circadian Rhythm ; Clock Proteins ; Epilepsy ; Epileptogenesis ; Mop3 ; Anatomy & Physiology
    E-ISSN: 1662-5137
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  • 9
    In: Brain, 2013, Vol. 136(10), pp.3140-3150
    Description: Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A , which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10 −9 , odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
    Subject(s): Mesial Temporal Lobe Epilepsy ; Mesial Temporal Sclerosis ; 〈Kwd〉〈Italic〉Scn1a〈/Italic〉〈/Kwd〉 ; Association ; Complex Genetics
    ISSN: 0006-8950
    E-ISSN: 1460-2156
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  • 10
    Language: English
    In: Brain research, 2002, Vol.936(1), pp.82-86
    Description: Maximal electroshock seizure threshold (MEST) is a classical measure of seizure sensitivity with a wide range of experimental applications. We determined MEST in nine inbred mouse strains and one congenic strain using a procedure in which mice are given one shock per day with an incremental (1 mA) current increase in each successive trial until a maximal seizure (tonic hindlimb extension) is elicited. C57BL/6J and DBA/2J mice exhibited the highest and lowest MEST, respectively, with the values of other strains falling between these two extremes. The relative rank order of MEST values by inbred strain (highest to lowest) is as follows: C57BL/6JCBA/J=C3H/HeJA/JBalb/cJ=129/SvIMJ=129/SvJAKR/JDBA/2J. Results of experiments involving a single electroconvulsive shock given to separate groups of mice at different current intensities suggest that determination of MEST by the method used is not affected by repeated sub-maximal seizures. Overall, results document a distinctive...
    Subject(s): Electroshock Seizure ; Mouse ; Complex Trait ; Strain Difference ; Disorders of the Nervous System ; Electroshock Seizure ; Mouse ; Complex Trait ; Strain Difference ; Anatomy & Physiology
    ISSN: 0006-8993
    E-ISSN: 1872-6240
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