Association between GABA(A) receptor subunit gene cluster and zolpidem-induced complex sleep behaviors in Han Chinese.
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ABSTRACT:
SUBMITTER: Tsai JH
PROVIDER: S-EPMC3543054 | biostudies-literature | 2013 Feb
REPOSITORIES: biostudies-literature
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Project description:Benzodiazepines and 'Z-drugs' (including zolpidem and zopiclone) are GABAA receptor (GABAAR) positive modulators commonly prescribed as hypnotics to treat insomnia and/or anxiety. However, alongside sedation, augmenting GABAAR function may also alter coordinated neuronal activity during sleep, thereby influencing sleep-dependent processes including memory consolidation. We used simultaneous recordings of neural population activity from the medial prelimbic cortex (PrL) and CA1 of the dorsal hippocampus (dCA1) of naturally sleeping rats to detail the effects of zolpidem on network activity during the cardinal oscillations of non-REM sleep. For comparison, we also characterized the effects of diazepam and 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP/gaboxadol), which acts predominantly at extra-synaptic GABAARs. Zolpidem and THIP significantly increased the amplitudes of slow-waves, which were attenuated by diazepam. Zolpidem increased hippocampal ripple density whereas diazepam decreased both ripple density and intrinsic frequency. While none of the drugs affected thalamocortical spindles in isolation, zolpidem augmented the temporal coordination between slow-waves and spindles. At the cellular level, analyses of spiking activity from 523 PrL and 579 dCA1 neurons revealed that zolpidem significantly enhanced synchronized pauses in cortical firing during slow-wave down states, while increasing correlated activity within and between dCA1 and PrL populations. Of the drugs compared here, zolpidem was unique in augmenting coordinated activity within and between hippocampus and neocortex during non-REM sleep. Zolpidem's enhancement of hippocampal-prefrontal coupling may reflect the cellular basis of its potential to modulate offline memory processing.
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Project description:Recently developed pharmacogenetic and optogenetic approaches, with their own advantages and disadvantages, have become indispensable tools in modern neuroscience. Here, we employed a previously described knock-in mouse line (GABA(A)R?2(77I)lox) in which the ?2 subunit of the GABA(A) receptor (GABA(A)R) was mutated to become zolpidem insensitive (?2(77I)) and used viral vectors to swap ?2(77I) with wild-type, zolpidem-sensitive ?2 subunits (?2(77F)). The verification of unaltered density and subcellular distribution of the virally introduced ?2 subunits requires their selective labelling. For this we generated six N- and six C-terminal-tagged ?2 subunits, with which cortical cultures of GABA(A)R?2(?/?) mice were transduced using lentiviruses. We found that the N-terminal AU1 tag resulted in excellent immunodetection and unimpaired synaptic localization. Unaltered kinetic properties of the AU1-tagged ?2 ((AU1)?2(77F)) channels were demonstrated with whole-cell patch-clamp recordings of spontaneous IPSCs from cultured cells. Next, we carried out stereotaxic injections of lenti- and adeno-associated viruses containing Cre-recombinase and the (AU1)?2(77F) subunit (Cre-2A-(AU1)?2(77F)) into the neocortex of GABA(A)R?2(77I)lox mice. Light microscopic immunofluorescence and electron microscopic freeze-fracture replica immunogold labelling demonstrated the efficient immunodetection of the AU1 tag and the normal enrichment of the (AU1)?2(77F) subunits in perisomatic GABAergic synapses. In line with this,miniature and action potential-evoked IPSCs whole-cell recorded from transduced cells had unaltered amplitudes, kinetics and restored zolpidem sensitivity. Our results obtained with a wide range of structural and functional verification methods reveal unaltered subcellular distributions and functional properties of ?2(77I) and (AU1)?2(77F) GABA(A)Rs in cortical pyramidal cells. This transgenic–viral pharmacogenetic approach has the advantage that it does not require any extrinsic protein that might endow some unforeseen alterations of the genetically modified cells. In addition, this virus-based approach opens up the possibility of modifying multiple cell types in distinct brain regions and performing alternative recombination-based intersectional genetic manipulations.
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Project description:Uterine leiomyomas (ULs) are the most common gynecological benign tumors originating from the myometrium. Prevalent mutations in the mediator complex subunit 12 (MED12) gene have been identified in ULs, and functional evidence has revealed that these mutations may promote the development of ULs. However, whether MED12 mutations are associated with certain clinical characteristics in ULs remains largely unknown. In the present study, the potential mutations of MED12 and its paralogous gene, mediator complex subunit 12-like (MED12L), were screened in 362 UL tumors from Han Chinese patients. A total of 158 out of 362 UL tumors (43.6%) were identified as harboring MED12 somatic mutations, and the majority of these mutations were restricted to the 44th residue. MED12 mutations were also observed in 2 out of 145 (1.4%) adjacent control myometrium. Furthermore, the mutation spectrum of MED12 in the concurrent leiomyomas was noticeably different. Correlation analysis of MED12 mutations with the available clinical features indicated that patients with mutated MED12 tended to have smaller cervical diameters. By contrast, no MED12L mutation was identified in the present samples. In summary, the present study demonstrated the presence of prevalent MED12 somatic mutations in UL samples, and the MED12 mutation was associated with smaller cervical diameters. The low mutation frequency of MED12 in adjacent control myometrium indicated that MED12 mutation may be an early event in the pathogenesis of ULs. Furthermore, MED12 mutation status in concurrent tumors from multiple leiomyomas supported several prior observations that the majority of these tumors arose independently.
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Project description:Although numerous studies have revealed significant associations between variants in the nicotinic acetylcholine receptors (nAChR) subunits and nicotine dependence (ND), only few studies were performed in Chinese subjects. Here, we performed association and interaction analysis for 20 single nucleotide polymorphisms (SNPs) in the CHRNB3-CHRNA6 gene cluster with ND in a Chinese Han population (N?=?5,055). We found nominally significant associations for all tested SNPs with ND measured by the Fagerström Test for Nicotine Dependence score; of these, 11 SNPs remained significant after Bonferroni correction for multiple tests (p?=?9?×?10-4~2?×?10-3). Further conditional analysis indicated that no other SNP was significantly associated with ND independent of the most-highly significant SNP, rs6474414. Also, our haplotype-based association analysis indicated that each haplotype block was significantly associated with ND (p?<?0.01). Further, we provide the first evidence of the genetic interaction of these two genes in affecting ND in this sample with an empirical p-value of 0.0015. Finally, our meta-analysis of samples with Asian and European origins for five SNPs in CHRNB3 showed significant associations with ND, with p-values ranging from 6.86?×?10-14 for rs13280604 to 6.50?×?10-8 for rs4950. This represents the first study showing that CHRNB3/A6 are highly associated with ND in a large Chinese Han sample.
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Project description:N-methyl-D-aspartate (NMDA) receptor has been indicated to be involved in the pathogenesis of Alzheimer's disease (AD). The NMDA receptor subunit 2b (NR2B) has attracted more attention due to its characteristic distribution and selective reduction in AD brain. The present study aimed to explore the association between NMDA gene polymorphism and AD.A total of 63 AD patients and 68 normal controls in Shanghai city were employed in this study. Genotype of C2664T variant (rs1806201) in the exon13 of GRIN2B gene was determined by gene sequencing.Among AD patients, 15 (23.6%) subjects were identified as C/C genotype, and 35 (55.6%) were identified as C/T genotype. The left 13 (20.6%) subjects were identified as T/T genotype. In normal controls, 15 (22.1%) subjects were identified as C/C genotype, 39 (57.4%) as C/T genotype and 14 (20.6%) as T/T genotype. The distribution frequency of neither GRIN2B C2664T genotype (P=0.895) nor allele (P=0.790) was significantly different between AD patients and normal controls, even when the subjects were stratified by gender and age of disease onset in AD patients.The results suggest that there is no relation between GRIN2B C2664T polymorphism and AD in Chinese Han population of Shanghai City.
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Project description:Sleep-related eating disorder (SRED) is characterised by eating episodes during the first period of the night sleep with partial loss consciousness, and amnesia. It can rarely be induced by some drugs, including zolpidem. We present a video report of a patient with a 1-year history of SRED caused by zolpidem causing important repercussions in the sleep structure and life quality. The night eating episodes ceased promptly with discontinuation of zolpidem. Upon the follow-up, the sleep structure improved and the daily consequences disappeared. As in few reported cases of zolpidem-induced SRED, our patient was suffering from the parasomnia for a long time before the diagnosis. Active exclusion of symptoms suggestive of SRED in patients under zolpidem treatment can avoid the deleterious effect of the sleep disorder.
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Project description:Recent genome-wide association studies (GWAS) have identified a strong association signal of microRNA137 host gene (MIR137) with schizophrenia. MIR137 dysfunction results in downregulation of presynaptic target gene complexin 1 (CPLX1) and impairs synaptic plasticity in the hippocampus. In this study, we aimed to investigate whether the variants of MIR137 and CPLX1 confer susceptibility to schizophrenia in Han Chinese. This study employed 736 patients with schizophrenia patients and 751 well-matched healthy subjects for genetic analysis, and genotyped 12 SNPs within MIR137 and CPLX1. SZDB database was used to performed brain eQTL analysis. There were no significant differences of CPLX1 expression in hippocampus, prefrontal cortex or stratum between the schizophrenia patients and control subjects. No significant differences were observed in allele and genotype frequencies in studied SNPs between the case and control groups. Gene interaction analysis showed that MIR137 SNP rs1625579 did not affect schizophrenia susceptibility in interaction with the CPLX1 polymorphic variants. Our findings do not support MIR137 and CPLX1 conferring susceptibility to schizophrenia in Han Chinese.
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Project description:ObjectiveTo investigate the relation between nicotinic acetylcholine receptor subunit (nAChR) genes and schizophrenia, and the relation between tag single nucleotide polymorphism (rs1317286, rs1044396, rs6494212, rs16969968, and rs684513) and schizophrenia in Han Chinese people.MethodsThe protein-protein interaction (PPI) network among nAChR protein and 350 proteins encoded by schizophrenia-related susceptibility genes was constructed through the String database to explore whether nAChR genes were associated with schizophrenia in these known databases. Then, five single nucleotide polymorphisms (SNPs) of CHRNA3 (rs1317286), CHRNA4 (rs1044396), CHRNA7 (rs6494212), and CHRNA5 (rs16969968, rs684513) were analyzed in a sample of 1,035 schizophrenic patients and 816 healthy controls. The interaction between the markers was analyzed using multifactor dimensionality reduction (MDR) software. Power analysis was performed using the Quanto program.ResultsThere are no significant differences in genotype or allele distribution were identified between the patients and controls (p>0.05). The haplotypes constructed by four markers rs1317286, rs6494212, rs16969968, and rs684513 were not associated with schizophrenia either. However, a significant association between models made of rs1317286, rs1044396, rs6494212, and rs684513 and schizophrenia was revealed in interaction analysis (p<0.05).ConclusionThe nAChR protein may have effects on the development of schizophrenia through the interaction with proteins encoded by schizophrenia-related susceptibility genes, but no relation was found between selected polymorphisms and schizophrenia in the collected Han Chinese people. However, interaction analysis suggested four-SNP model has an important effect on schizophrenia.
| S-EPMC8542753 | biostudies-literature
Project description:BackgroundTTC32-WDR35 gene cluster has been genome-wide significantly associated with coronary artery disease (CAD). However, the common variants in this region contributing to CAD risk remain elusive.MethodsWe performed a case-control study enrolling 935 CAD cases and 935 age-sex-frequency-matched controls from unrelated southwest Chinese Han population. Five variants were determined by TaqMan assay.ResultsThis study indicated that rs721932 CG genotype was associated with CAD risk (OR = 0.68, 95% CI: 0.54-0.86; P = .001). Stratified analysis showed that the risk associated with rs12617744 AA genotype was robust in male (OR = 0.62, 95% CI: 0.42-0.93, P = .02). The gene dosage of the risk allele at rs12617744 showed a significant association with left circumflex artery disease (P = .027) and the number of vascular lesions in patients (P = .034). Moreover, the gene dosage of rs721932 risk allele was associated with vascular lesion numbers (P = .048) and the progression of CAD (P = .028). Compared with carriers of major alleles, the AA genotype of rs12617744 and GG genotype of rs721932 were both associated with plasma HDL level (P = .009 and 0.004, respectively). Expression quantitative trait locus (eQTL) results showed significantly different TTC32 expression of subjects as a function of SNPs (rs2278528, rs7594214, and rs721932) genotype in the artery. Besides, FPRP analysis did support the strong links between polymorphisms and CAD risk.ConclusionsSNP rs721932 at TTC32-WDR35 Gene Cluster was associated with CAD risk, and rs12617744 was associated with the risk of CAD among males. Both SNPs may contribute to the regulation of plasma HDL levels and possibly to the severity of CAD in Chinese Han population.
| S-EPMC7891520 | biostudies-literature
Project description:ObjectivesTo estimate the relationship between sleep quality and depression, among Han and Manchu ethnicities, in a rural Chinese population.MethodsA sample of 8,888 adults was selected using a multistage cluster and random sampling method. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Depressive symptoms were assessed via the Center for Epidemiological Survey, Depression Scale (CES-D). Logistic regression was conducted to assess associations between sleep quality and depression.ResultsThe prevalence of poor sleep quality and depression in the Manchus (20.74% and 22.65%) was significantly lower than that in the Hans (29.57% and 26.25%), respectively. Depressive participants had higher odds ratios of global and all sub PSQI elements than non-depressive participants, both among the Hans and the Manchus. Additive interactions were identified between depressive symptoms and ethnicity with global and four sub-PSQI elements, including subjective sleep quality, sleep disturbance, use of sleep medication and daytime dysfunction.ConclusionsThe findings revealed that the prevalence of poor sleep quality and depression among the Hans was greater than among the Manchus. Depression was associated with higher odds of poor sleep quality.
| S-EPMC6922383 | biostudies-literature