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1.
Mol Brain ; 14(1): 68, 2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33845872

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by the segmental deletion of human chromosome 22. This chromosomal deletion is known as high genetic risk factors for various psychiatric disorders. The different deletion types are identified in 22q11.2DS patients, including the most common 3.0-Mb deletion, and the less-frequent 1.5-Mb and 1.4-Mb deletions. In previous animal studies of psychiatric disorders associated with 22q11.2DS mainly focused on the 1.5-Mb deletion and model mice mimicking the human 1.5-Mb deletion have been established with diverse genetic backgrounds, which resulted in the contradictory phenotypes. On the other hand, the contribution of the genes in 1.4-Mb region to psychiatric disorders is poorly understood. In this study, we generated two mouse lines that reproduced the 1.4-Mb and 1.5-Mb deletions of 22q11.2DS [Del(1.4 Mb)/+ and Del(1.5 Mb)/+] on the pure C57BL/6N genetic background. These mutant mice were analyzed comprehensively by behavioral tests, such as measurement of locomotor activity, sociability, prepulse inhibition and fear-conditioning memory. Del(1.4 Mb)/+ mice displayed decreased locomotor activity, but no abnormalities were observed in all other behavioral tests. Del(1.5 Mb)/+ mice showed reduction of prepulse inhibition and impairment of contextual- and cued-dependent fear memory, which is consistent with previous reports. Furthermore, apparently intact social recognition in Del(1.4 Mb)/+ and Del(1.5 Mb)/+ mice suggests that the impaired social recognition observed in Del(3.0 Mb)/+ mice mimicking the human 3.0-Mb deletion requires mutations both in 1.4-Mb and 1.5 Mb regions. Our previous study has shown that Del(3.0 Mb)/+ mice presented disturbance of behavioral circadian rhythm. Therefore, we further evaluated sleep/wakefulness cycles in Del(3.0 Mb)/+ mice by electroencephalogram (EEG) and electromyogram (EMG) recording. EEG/EMG analysis revealed the disturbed wakefulness and non-rapid eye moving sleep (NREMS) cycles in Del(3.0 Mb)/+ mice, suggesting that Del(3.0 Mb)/+ mice may be unable to maintain their wakefulness. Together, our mouse models deepen our understanding of genetic contributions to schizophrenic phenotypes related to 22q11.2DS.

2.
Behav Brain Res ; 408: 113284, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819533

RESUMO

Habitual smoking in patients with schizophrenia (SCZ) is considered to improve their own psychoses or to develop a vulnerability to psychological dependence on (-)-nicotine ([-]-NIC) by stimulating nicotinic acetylcholine receptors (nAChRs) in the central nervous system. In the present study, we investigated whether habitual smoking is due to get therapeutic effect or to psychological dependence and which nAChR subunits are associated with them using mice that were repeatedly administered phencyclidine (PCP: 10 mg/kg/day, s.c. for 14 days) as SCZ-like model mice. Mice that were repeatedly administered PCP showed impairments in social or cognitive behaviors; decreased expression of α7 and/or α4 nAChR subunits in the prefrontal cortex (PFC); and increased expression of α7, α4, and ß2 nAChR subunits in the nucleus accumbens (NAc). These changes were attenuated by repeated administration of (-)-NIC. The attenuating effects on behavioral impairments were prevented by a selective α7 nAChR antagonist and a selective α4ß2 nAChR antagonist. At non- or weak effective dose by themselves, co-administration of (-)-NIC (0.03 mg/kg) and risperidone (0.03 mg/kg) showed synergistic effects on behavioral impairments in PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC in the PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC and attenuating effect on haloperidol-induced catalepsy in the PCP-administered mice. Our findings suggest that habitual smoking in SCZ might be attributed to get therapeutic and reduce side effects mediated by α7 and α4ß2 nAChR activation by (-)-NIC.

3.
Psychogeriatrics ; 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33644945

RESUMO

BACKGROUND: The use of benzodiazepines (BZDs) causes delirium, especially in elderly people. For this reason, suvorexant has been recommended as the first-line hypnotic in elderly patients. The aim of this study was to determine whether the first-line use of suvorexant, instead of BZDs, decreases referrals for delirium in elderly patients. METHODS: Since May 2016 at Nagoya Ekisaikai Hospital, suvorexant has been recommended as the first-line hypnotic instead of BZDs. In May 2017, suvorexant was adopted as the first-line hypnotic. The number of delirium cases referred to psychiatry was compared among three consecutive periods: period A (May 2015-April 2016), during which BZDs were mainly used for insomnia; period B (May 2016-April 2017), during which the use of suvorexant was recommended instead of BZDs; and period C (May 2017-April 2018), during which suvorexant was principally adopted as the first-line hypnotic for insomnia. Potential confounding factors that may affect the development of delirium were also examined during the three periods. RESULTS: The number of delirium referral cases in elderly patients in each period decreased, from 133 in period A to 86 in period B and 53 in period C. The rate of delirium referral cases decreased significantly every year (P = 9.02 × 10-10 ). Almost no significant confounding factors other than hypnotics were detected during the three periods. CONCLUSION: The referrals for delirium in elderly patients decreased significantly after the hypnotic was changed from BZDs to suvorexant.

4.
Sci Rep ; 11(1): 7039, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782431

RESUMO

Sleep disturbances and cognitive decline are common in older adults. We aimed to investigate the effects of the total sleep time (TST) and sleep-wake rhythm on executive function and working memory in older adults. In 63 older participants, we measured the TST, wake after sleep onset (WASO), and sleep timing (midpoint between bedtime and wake-up time) using actigraphy. Executive function was evaluated with the trail making test B (TMT-B) and Wisconsin card sorting test (WCST). The number of back task (N-back task) was used to measure working memory. Participants with a TST ≥ 8 h had a significantly lower percentage of correct answers (% correct) on the 1-back task than those with a TST < 8 h. The % correct on the 1-back task was significantly correlated with the TST, WASO, and sleep timing. Multiple regression analyses revealed that the TST and sleep timing were significant factors of the % correct on the 1-back task. The TMT-B score was significantly correlated with the sleep timing. Category achievement on the WCST was significantly correlated with the standard deviation of the sleep timing. Therefore, a long sleep time and an irregular sleep-wake rhythm could have adverse effects on executive function and working memory in older people.

5.
Hum Psychopharmacol ; 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33743182

RESUMO

BACKGROUND: Various factors affecting the development of delirium have been identified. However, the associations between the severity of delirium and potentially related factors have not been adequately investigated. The aim of the present study was to explore factors associated with the severity of delirium and to identify the reversible contributing factors. METHODS: A total of 577 patients with delirium referred to the Department of Psychiatry during the 5 years from May 2015 to April 2020 at a general hospital were included. The Delirium Rating Scale-revised-98 (DRS-R-98) was used to measure the severity of delirium. Multiple regression analysis was used to determine whether individual factors were associated with the severity of delirium. RESULTS: Intensive care unit admission (p = 0.003), use of benzodiazepines (p = 0.01), dementia (p = 0.02), and older age (p = 0.045) were all positively associated the severity of delirium, while use of ß-blockers (p = 0.001) was negatively associated with the severity of delirium. CONCLUSIONS: Reversible contributing factors, that is use of benzodiazepines, should be avoided as much as possible, especially in elderly patients or patients with dementia or patients who need critical care in ICU. Reducing the dose of benzodiazepines or switching them to other drugs should be a priority.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33615745

RESUMO

Abnormal eye movements are often associated with psychiatric disorders. Eye movements are sensorimotor functions of the brain, and aging and sex would affect their characteristics. A precise understanding of normal eye movements is required to distinguish disease-related abnormalities from natural differences associated with aging or sex. To date, there is no multicohort study examining age-related dependency and sex effects of eye movements in healthy, normal individuals using large samples to ensure the robustness and reproducibility of the results. In this study, we aimed to provide findings showing the impact of age and sex on eye movement measures. The present study used eye movement measures of more than seven hundred healthy individuals from three large independent cohorts. We herein evaluated eye movement measures quantified by using a set of standard eye movement tests that have been utilized for the examination of patients with schizophrenia. We assessed the statistical significance of the effects of age and sex and its reproducibility across cohorts. We found that 4-18 out of 35 eye movement measures were significantly correlated with age, depending on the cohort, and that 10 of those, which are related to the fixation and motor control of smooth pursuit and saccades, showed high reproducibility. On the other hand, the effects of sex, if any, were less reproducible. The present results suggest that we should take age into account when we evaluate abnormalities in eye movements.

7.
Mol Autism ; 12(1): 15, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622389

RESUMO

BACKGROUND: Oxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown. METHODS: The current study explored metabolites representing the molecular mechanisms of oxytocin's efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial. RESULTS: Among the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (PFDR = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (PFDR = 0.006, r = - 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 0.032, r = 0.415, N = 37). LIMITATIONS: The metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes. CONCLUSION: Our findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin's efficacy. TRIAL REGISTRATION: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703 ) (UMIN000015264).

8.
Transl Psychiatry ; 11(1): 49, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446640

RESUMO

The cerebral cortex is composed of multiple cortical areas that exert a wide variety of brain functions. Although human brain neurons are genetically and areally mosaic, the three-dimensional structural differences between neurons in different brain areas or between the neurons of different individuals have not been delineated. Here we report a nanometer-scale geometric analysis of brain tissues of the superior temporal gyrus of schizophrenia and control cases. The results of the analysis and a comparison with results for the anterior cingulate cortex indicated that (1) neuron structures are significantly dissimilar between brain areas and that (2) the dissimilarity varies from case to case. The structural diverseness was mainly observed in terms of the neurite curvature that inversely correlates with the diameters of the neurites and spines. The analysis also revealed the geometric differences between the neurons of the schizophrenia and control cases. The schizophrenia cases showed a thin and tortuous neuronal network compared with the controls, suggesting that the neuron structure is associated with the disorder. The area dependency of the neuron structure and its diverseness between individuals should represent the individuality of brain functions.

9.
Sci Rep ; 11(1): 1155, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441847

RESUMO

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

10.
Neurochem Int ; 144: 104954, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33388358

RESUMO

Reelin, an extracellular matrix protein, is secreted by Cajal-Retzius cells and plays crucial roles in the development of brain structures and neuronal functions. Reductions in Reelin cause the brain dysfunctions associated with mental disorders, such as schizophrenia. A recent genome-wide copy number variation analysis of Japanese schizophrenia patients identified a novel deletion in RELN encoding Reelin. To clarify the pathophysiological role of the RELN deletion, we developed transgenic mice carrying the RELN deletion (Reln-del) and found abnormalities in their brain structures and social behavior. In the present study, we performed an in vitro analysis of Reelin expression, intracellular Reelin signaling, and the morphology of primary cultured cortical neurons from wild-type (WT) and Reln-del mice. Reelin protein levels were lower in Reln-del neurons than in WT neurons. Dab1 expression levels were significantly higher in Reln-del neurons than in WT neurons, suggesting that Reelin signaling was decreased in Reln-del neurons. Reelin was mainly expressed in γ-aminobutyric acid (GABA)-ergic inhibitory neurons, but not in parvalbumin (PV)-positive neurons. A small proportion of Ca2+/calmodulin-dependent protein kinase II α subunit (CaMKIIα)-positive excitatory neurons also expressed Reelin. In comparisons with WT neurons, significant decreases were observed in neurite lengths and branch points as well as in the number of postsynaptic density protein 95 (PSD95) immunoreactive puncta in Reln-del neurons. A disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS-3) is a protease that inactivates Reelin by cleavage at the N-t site. The knockdown of ADAMTS-3 by short hairpin RNAs suppressed Reelin cleavage in conditioned medium and reduced Dab1 expression, indicating that Reelin signaling was enhanced in the primary cultured cortical neurons of WT and heterozygous Reln-del. Accordingly, the inhibition of ADAMTS-3 may be a potential candidate in the clinical treatment of schizophrenia by enhancing Reelin signaling in the brain.

11.
Neurosci Res ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33460682

RESUMO

Stress vulnerability and pathogenic mechanisms in stress-related disorders are strongly associated with the functions of serotonin transporter (SERT). SERT phosphorylation induces a reduction of the serotonin (5-HT, 5-hydroxytryptamine) transport properties, its phosphorylation regulated by protein kinase C (PKC). However, the functional relationship between regulated SERT activity by PKC and stress vulnerability remains unclear. Here, we investigated whether the functional regulation of SERT by PKC was involved in stress vulnerability using mice exposed to twice-swim stress that exhibited the impairment of social behaviors. The mild-swim stress (6 min) given just before the social interaction test did not affect the social behaviors of mice. However, mice exposed to strong-swim stress (15 min) became vulnerable to the mild-swim stress, and subsequent social behaviors were impaired. Chelerythrine, a PKC inhibitor, exacerbated decreased sociality in mice exposed to acute mild-swim stress. Phorbol 12-myristate 13-acetate (PMA), a PKC activator, ameliorated the impairment of social behaviors in mice exposed to twice-swim stress. Phosphorylated PKCßI or SERT and 5-HT levels were decreased in the prefrontal cortex of twice-stressed mice. These decreases were attenuated by PMA. Our findings demonstrate that mice exposed to twice-swim stress developed stress vulnerability, which may be involved in the regulation of SERT phosphorylation and 5-HT levels accompanying PKCßI activity.

12.
Mol Brain ; 14(1): 21, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33482876

RESUMO

We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Special attention was paid to one patient carrying a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion in the other allele. Accordingly, we generated a mouse model (Arhgap10 S490P/NHEJ mice) carrying a missense variant and a coexisting frameshift mutation. We examined the spatiotemporal expression of Arhgap10 mRNA in the brain and found the highest expression levels in the cerebellum, striatum, and nucleus accumbens (NAc), followed by the frontal cortex in adolescent mice. The expression levels of phosphorylated myosin phosphatase-targeting subunit 1 and phosphorylated p21-activated kinases in the striatum and NAc were significantly increased in Arhgap10 S490P/NHEJ mice compared with wild-type littermates. Arhgap10 S490P/NHEJ mice exhibited a significant increase in neuronal complexity and spine density in the striatum and NAc. There was no difference in touchscreen-based visual discrimination learning between Arhgap10 S490P/NHEJ and wild-type mice, but a significant impairment of visual discrimination was evident in Arhgap10 S490P/NHEJ mice but not wild-type mice when they were treated with methamphetamine. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of Arhgap10 S490P/NHEJ mice. Taken together, these results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality of neurons in the striatum and NAc, which may be associated with vulnerability of cognition to methamphetamine treatment.

13.
EBioMedicine ; 63: 103138, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341442

RESUMO

BACKGROUND: The chromosome 22q11.2 deletion is an extremely high risk genetic factor for various neuropsychiatric disorders; however, the 22q11.2 deletion-related brain pathology in humans at the cellular and molecular levels remains unclear. METHODS: We generated iPS cells from healthy controls (control group) and patients with 22q11.2 deletion (22DS group), and differentiated them into dopaminergic neurons. Semiquantitative proteomic analysis was performed to compare the two groups. Next, we conducted molecular, cell biological and pharmacological assays. FINDINGS: Semiquantitative proteomic analysis identified 'protein processing in the endoplasmic reticulum (ER)' as the most altered pathway in the 22DS group. In particular, we found a severe defect in protein kinase R-like endoplasmic reticulum kinase (PERK) expression and its activity in the 22DS group. The decreased PERK expression was also shown in the midbrain of a 22q11.2 deletion mouse model. The 22DS group showed characteristic phenotypes, including poor tolerance to ER stress, abnormal F-actin dynamics, and decrease in protein synthesis. Some of phenotypes were rescued by the pharmacological manipulation of PERK activity and phenocopied in PERK-deficient dopaminergic neurons. We lastly showed that DGCR14 was associated with reduction in PERK expression. INTERPRETATION: Our findings led us to conclude that the 22q11.2 deletion causes various vulnerabilities in dopaminergic neurons, dependent on PERK dysfunction. FUNDING: This study was supported by the AMED under grant nos JP20dm0107087, JP20dm0207075, JP20ak0101113, JP20dk0307081, and JP18dm0207004h0005; the MEXT KAKENHI under grant nos. 16K19760, 19K08015, 18H04040, and 18K19511; the Uehara Memorial Foundation under grant no. 201810122; and 2019 iPS Academia Japan Grant.

14.
J Hum Genet ; 66(1): 25-37, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32958875

RESUMO

Copy number variants (CNVs), defined as genome sequences of ≥50 bp that differ in copy number from that in a reference genome, are a common form of structural variation. Germline CNVs account for some of the missing heritability that single nucleotide polymorphisms could not account for. Recent technological advances have had a huge impact on CNV research. Microarray technology enables relatively low-cost, high-throughput, genome-wide measurements, and short-read sequencing technology enables the detection of short CNVs that cannot be detected by microarrays. As a result, large-scale genetic studies have been able to identify a variety of common and rare germline CNVs and their associations with diseases. Rare germline CNVs have been reported to be associated with neuropsychiatric disorders. In this review, we focused on germline CNVs and briefly described their functional characteristics, formation mechanisms, detection methods, related databases, and the latest findings. Finally, we introduced recent large-scale genetic studies to assess associations of CNVs with diseases, especially psychiatric disorders, and discussed the use of CNV-based animal models to investigate the molecular and cellular mechanisms underlying these disorders. The development and implementation of improved detection methods, such as long-read single-molecule sequencing, are expected to provide additional insight into the molecular basis of psychiatric disorders and other complex diseases, thus facilitating basic and clinical research on CNVs.

16.
Hum Genome Var ; 7(1): 37, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33298905

RESUMO

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

17.
Transl Psychiatry ; 10(1): 421, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33279929

RESUMO

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

18.
Neurosci Res ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33316300

RESUMO

Recent rapid progress in genome analysis and large-scale consortia has made it possible to discover variants with a variety of allele frequencies and effect sizes associated with psychiatric disorders. Among psychiatric disorder-susceptibility variants, rare variants with large effect sizes detected by sequencing analysis or array comparative genomic hybridization would be particularly useful for elucidating pathophysiology by developing disease models, such as genome-edited mouse or induced pluripotent stem cells. In the last decade, investigations of rare variants with large effect size have revealed an important role of neurodevelopment in the pathogenesis of psychiatric disorders. In future research, integration of recent evidence concerning the contribution of the immune system or gut microbiota will enhance our understanding of psychiatric disorders and facilitate novel drug development.

19.
J Sleep Res ; : e13273, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33372341

RESUMO

Key clinical symptoms observed among individuals with psychiatric disorders include difficulty falling asleep or maintaining sleep, poor sleep quality and nightmares. Those suffering from sleep disorders often present with symptoms of discontent with regard to sleep quality, timing and quantity, and these symptoms have an adverse impact on function and quality of life. A minimally invasive technique would be preferable in patients with psychiatric disorders, who tend to be sensitive to environmental change. Accordingly, we evaluated the performance of Zmachine Insight Plus, an ambulatory electroencephalography sleep monitor, in patients with psychiatric disorders. One hundred and three patients undergoing polysomnography were enrolled in this study. Zmachine Insight Plus was performed simultaneously with polysomnography. Total sleep time, sleep efficiency, wake after sleep onset, rapid eye movement (REM) sleep, light sleep (stages N1 and N2) and deep sleep (stage N3) were assessed. Total sleep time, sleep efficiency, wake after sleep onset, REM sleep duration and non-REM sleep duration of Zmachine Insight Plus showed a significant correlation with those of polysomnography. Lower sleep efficiency and increased frequency of waking after sleep onset, the arousal index and the apnea-hypopnea index on polysomnography were significantly associated with the difference in sleep parameters between the two methods. Among patients with psychiatric disorders who are sensitive to environmental change, Zmachine Insight Plus would be a useful technique to objectively evaluate sleep quality.

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