Expression alteration of Neuroligin family gene in attention deficit and hyperactivity disorder and autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopment disorder with social and communicational deficiency, language impairment, and ritualistic behaviors. Attention deficit hyperactivity disorder (ADHD) is a pediatric psychiatric disorder with symptoms, including attention deficit, hyperactivity, and impulsiveness. ADHD is a childhood-onset disorder that can persist into adult life. Neuroligins are post-synaptic cell-adhesion molecules that connect neurons and have an essential role in the mediation of trans-synaptic signaling and shaping the synapse and circuits and neural network functioning. AIMS: Present study aimed to shed light on the role of the Neuroligin gene family in ASD and ADHD. METHODS AND PROCEDURES: mRNA levels of the Neuroligin gene family (NLGN1, NLGN2, NLGN3, and NLGN4X) were studied in the peripheral blood of 450 unrelated ASD patients, 450 unrelated ADHD patients, and the normal group included 490 unrelated non-psychiatric children by quantitative PCR. Also, clinical situations were considered. OUTCOMES AND RESULTS: Results showed that mRNA levels of NLGN1, NLGN2, and NLGN3 were significantly down-regulated in the ASD group vs. control subjects. In ADHD, a significant reduction of NLGN2 and NLGN3 was detected in comparison with normal children. A comparison of ASD and ADHD subjects revealed that NLGN2 was significantly down-regulated in ASD subjects. CONCLUSIONS: The Neuroligin family gene may play an essential role in the etiology of ASD and ADHD and thus be a source for a better understanding of neurodevelopment disorders. IMPLICATIONS: Similar patterns of deficiency of Neuroligin family genes in ASDs and ADHDs may indicate the role of these genes in functions that have been affected in both disorders.

Nrf2 signaling in diabetic nephropathy, cardiomyopathy and neuropathy: Therapeutic targeting, challenges and future prospective.

Western lifestyle contributes to an overt increase in the prevalence of metabolic anomalies including diabetes mellitus (DM) and obesity. Prevalence of DM is rapidly growing worldwide, affecting many individuals in both developing and developed countries. DM is correlated with the onset and development of complications with diabetic nephropathy (DN), diabetic cardiomyopathy (DC) and diabetic neuropathy being the most devastating pathological events. On the other hand, Nrf2 is a regulator for redox balance in cells and accounts for activation of antioxidant enzymes. Dysregulation of Nrf2 signaling has been shown in various human diseases such as DM. This review focuses on the role Nrf2 signaling in major diabetic complications and targeting Nrf2 for treatment of this disease. These three complications share similarities including the presence of oxidative stress, inflammation and fibrosis. Onset and development of fibrosis impairs organ function, while oxidative stress and inflammation can evoke damage to cells. Activation of Nrf2 signaling significantly dampens inflammation and oxidative damage, and is beneficial in retarding interstitial fibrosis in diabetic complications. SIRT1 and AMPK are among the predominant pathways to upregulate Nrf2 expression in the amelioration of DN, DC and diabetic neuropathy. Moreover, certain therapeutic agents such as resveratrol and curcumin, among others, have been employed in promoting Nrf2 expression to upregulate HO-1 and other antioxidant enzymes in the combat of oxidative stress in the face of DM.

The first genome-wide association study of internet addiction; Revealed substantial shared risk factors with neurodevelopmental psychiatric disorders.

BACKGROUND: Internet addiction disorder (IAD) is listed as a disorder requiring further studies in the diagnostic and statistical manual of mental disorders (DSM-V). Psychological studies showed significant co-morbidity of IAD with depression, alcohol abuse, and anxiety disorder. Etiology and genetic bases of IAD are unclear. AIMS: Present study aimed to investigate the genetic, psychological, and cognitive bases of a tendency to internet addiction. METHODS AND PROCEDURES: DNA was extracted from blood samples of IADs (N = 16,520) and 18,000 matched non-psychiatric subjects. Genotyping for the subjects was performed using SNP Array. Psychological, neuropsychological, and neurological characteristics were conducted. OUTCOMES AND RESULTS: Seventy-two SNPs in 24 genes have been detected significantly associated with IAD. Most of these SNPs were risk factors for psychiatric disorders. Most similarity detected with autism spectrum disorder, bipolar disorder and schizophrenia. Higher anxiety, stress, and neuroticism and deficits in working memory, attention, planning, and processing speed were detected in IADs. CONCLUSIONS: This study is the first genome-wide association study of IAD that showed strong shared genetic bases with neurodevelopmental disabilities and psychiatric disorders. IMPLICATIONS: Genetic risk factors in IADs may cause several cognitive and neurodevelopmental brain function abnormalities, which lead to excessive Internet usage. It may suggest that IAD could be a marker for vulnerability to developmental psychiatric disorders.

Cross-country comparison of parental reports and objective measures of sleep patterns of typically developing children and autistic children between the UK and South Korea.

Sleep duration and disturbances in typically developing (TD) children have been found to vary across countries. Given the impact of culture on sleep patterns in TD children, it is also necessary to examine the impact of culture on sleep patterns in children with atypical development. However, previous studies have often relied only on parent reports of children's sleep. Hence, the present study conducted a cross-cultural comparison of sleep duration and disturbances of school-aged TD children and autistic children in the UK and South Korea (hereafter Korea) using both subjective and objective sleep measurements. Cultural differences were observed in both actigraphy measures and parent reports of children's sleep duration and disturbances. Both TD children and autistic children in Korea had a later bedtime, later getting up time and shorter nocturnal sleep duration than their peers in the UK (p < .05). Furthermore, greater parent-reported sleep disturbances were reported in TD children in Korea compared to TD children in the UK and in autistic children in the UK compared to autistic children in Korea. Correlational analyses indicated that most parent-reported measures of children's sleep did not significantly correlate with objective measures and child reports, suggesting that studies on children's sleep can benefit by collecting data from multiple sources. Taken together, these findings suggest a cultural influence on sleep duration and disturbances of both TD children and autistic children. This study raises questions for further research to identify factors underlying cultural differences in children's sleep duration and disturbances.

FOXP2 down expression is associated with executive dysfunctions and electrophysiological abnormalities of brain in Autism spectrum disorder; a neuroimaging genetic study.

Background and aims: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language impairment, and challenges with social interaction, communication, and repetitive behaviors. Although genetics are a primary cause of ASD, the exact genes and molecular mechanisms involved in its pathogenesis are not completely clear. The FOXP2 gene encodes a transcription factor that is known for its major role in language development and severe speech problems. The present study aimed to evaluate the role of FOXP2 in ASD etiology, executive functions, and brain activities. Methods: In the present study, we recruited 450 children with ASD and 490 neurotypical control children. Three domains of executive functions (working memory, response inhibition, and vigilance) were assessed. In addition, five-minute eyes closed electroencephalography was obtained from some of the children with ASD and neurotypical children. DNA sequence and expression level of FOXP2 in blood samples of children with ASD and the control group were evaluated by using sequencing and Real-time PCR, respectively. Results: The results showed no mutations but a significant down expression of FOXP2 genes in children with ASD vs. neurotypical children. Several cognitive and executive function deficiencies were detected in children with ASD. Low alpha and gamma bands in the frontal lobe and high theta bands in the occipital lobe were revealed in children with ASD. We also found several correlations between FOXP2 expression levels and clinical assessments. Conclusions: Our finding revealed the down expression of FOXP2, which could be considered as a biomarker for ASD as well as cognitive and executive dysfunction. Based on brain mapping data, FOXP2 may be related to the theta wave abnormality of children with ASD. FOXP2 may be considered a target of novel treatment to improve memory and executive functions. Implications: Our findings highlight the role of FOXP2 mRNA level in ASD etiology, executive functions, and brain wave frequencies.

Short report of an Iranian Prenatal Methamphetamine Exposure effect cohort showed DNA methylation alteration of mitochondria function associated genes.

BACKGROUND: Use of Methamphetamine during pregnancy is significant public health concern since it affects the development of the brain and poor behavioral outcomes in children. Prenatal methamphetamine exposure (PME) may cause developmental disabilities and several gene expression and molecular pathways alterations. In the present study, DNA methylation of Propionyl-CoA Carboxylase subunit Beta (PCCB) and Protocadherin Alpha 12 (PCDHA12) genes were assessed in two groups of three-year-old children, those exposed to PME and healthy control children. AIMS: Clarification of PME role in methylation level of two mitochondria function associated genes; PCCB and PCDHA12. METHODS AND PROCEDURES: In this study, 2629 children with PME (1531male, 1098 female) and 3523(2077male, 1446 female) control children were recruited based on maternal self-report of prenatal exposure. Genomic DNA extracted from peripheral blood and pyrosequencing was used to determine the association between prenatal MA exposure and methylation in nine CpG sites of PCCB and PCDHA12 genes. OUTCOMES AND RESULTS: Prenatal methamphetamine exposure was associated with significant DNA hypomethylation of four out of five CpG sites in the PCCB gene and three out of four CpG sites in the PCDHA12 gene. Also, significant hypomethylation in the biding site of p53 transcription factor in PCCB gene was detected in children with PME. CONCLUSIONS AND IMPLICATIONS: Prenatal methamphetamine exposure is related to epigenetic alterations in PCCB and PCDHA12, as important mitochondria function associated genes. Detected hypomethylation in these genes was reported in neurodevelopmental and bioenergetics disabilities. It seems that PME could cause mitochondrial dysfunctions associated with developmental abnormalities. What this paper adds?

Detection of six novel de novo mutations in individuals with low resilience to psychological stress.

Genetic bases of psychological stress resilience have been studied previously, but mechanisms and genetic variants which are involved in stress resilience are still unclear. The present study aimed to evaluate the associations between variants in dopaminergic pathway genes with stress resilience. Subjects of the present study were divided into four groups. Group A included persons with normal reactions to major life events stressors; group B included persons with an acute stress reaction to major life events stressor; group C included persons with normal reactions to Crises/catastrophes stressors, and group D included persons with an acute stress reaction to Crises/catastrophes stressors. DNA was extracted from the subject's blood, and the entire length of 14 genes DRD1, DRD2, DRD3, DRD4, DRD5, COMT, DBH, TH, MAOA, DDC, DAT, 5-HTT, BDNF, and GDNF were sequenced by automated sequencers ABI 3700. Results showed 24 point mutations in 12 genes, including 16 SNPs and six novel mutations, which were significantly correlated to low-stress resilience. Most of the SNPs were known as risk alleles in psychiatric disorders. Several associations were found between genetic variants and psychological characteristics. Findings suggest dopaminergic as an important pathway in stress and stress resilience also indicated shared genetic bases between low-stress resilience and several psychiatric disorders.

Neuregulin1 types mRNA level changes in autism spectrum disorder, and is associated with deficit in executive functions.

BACKGROUND: Autism spectrum disorder (ASD) is a pediatric heterogeneous psychiatric and neurodevelopmental disorder with social and communication deficits, language impairment and ritualistic or repetitive behaviors. ASD has significant genetic bases but candidate genes and molecular mechanisms of disorder are not clarified. Neuregulin1 (NRG1) gene, located in 8p12 is involved in development of central nervous system and was indicated as candidate gene in schizophrenia. METHODS: mRNA level of types I, II and III of NRG1 gene were studied in peripheral blood of 1540 ASD patients (IQ > 70) and 1490 control children by quantitative Real Time PCR. Also three domains of executive functions (working memory, response inhibition and vigilance) were examined in all subjects. FINDINGS: All three types were significantly down regulated in ASD patients. Significant deficiencies in executive functions (EF) were found in ASD patients. EF deficiencies mostly were associated with down expression of mRNA level of types I and III. Also correlations were found between NRG1 expression with gender and severity of ASD symptoms. INTERPRETATIONS: Findings primarily have been suggested involvement of NRG1 in etiology of ASD. Also correlation of NRG1 mRNA level with EF deficiencies could shed lights on EF mechanisms and may suggest targeted treatments to improve particular executive functions. FUND: Young researchers and elites club funded the project due to the annual grant of special talents of Club that gave to Arvin Haghighatfard.

Time estimation and beta segregation: An EEG study and graph theoretical approach.

Elucidation of the neural correlates of time perception constitutes an important research topic in cognitive neuroscience. The focus to date has been on durations in the millisecond to seconds range, but here we used electroencephalography (EEG) to examine brain functional connectivity during much longer durations (i.e., 15 min). For this purpose, we conducted an initial exploratory experiment followed by a confirmatory experiment. Our results showed that those participants who overestimated time exhibited lower activity of beta (18-30 Hz) at several electrode sites. Furthermore, graph theoretical analysis indicated significant differences in the beta range (15-30 Hz) between those that overestimated and underestimated time. Participants who underestimated time showed higher clustering coefficient compared to those that overestimated time. We discuss our results in terms of two aspects. FFT results, as a linear approach, are discussed within localized/dedicated models (i.e., scalar timing model). Second, non-localized properties of psychological interval timing (as emphasized by intrinsic models) are addressed and discussed based on results derived from graph theory. Results suggested that although beta amplitude in central regions (related to activity of BG-thalamocortical pathway as a dedicated module) is important in relation to timing mechanisms, the properties of functional activity of brain networks; such as the segregation of beta network, are also crucial for time perception. These results may suggest subjective time may be created by vector units instead of scalar ticks.

Low resilience to stress is associated with candidate gene expression alterations in the dopaminergic signalling pathway.

BACKGROUND: In stressful situations, a person's ability to appropriately complete tasks with minimal anxiety is known as stress resilience. Genetic variants in neuropeptide Y, Corticotropin releasing hormone receptor 1 (CRHR1), and serotonin transporter have been previously reported to be associated with low resilience, but the relationship between low resilience and the dopaminergic signalling pathway is not well understood. Here, we aimed to describe the association between comprehensive psychological characteristics and messenger RNA levels of dopamine receptor D1 (DRD1), dopamine receptor D2 (DRD2), dopamine receptor D3 (DRD3), dopamine receptor D4 (DRD4), dopamine receptor D5 (DRD5), COMT, Dopamine Beta-Hydroxylase (DBH), Tyrosine hydroxylase (TH), monoamine oxidase A (MAOM), dopa decarboxylase (DDC), dopamine transporter (DAT), serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) genes based on peripheral blood samples from 400 subjects who react differently to major life event stressors. The blood samples were analyzed by quantitative real-time polymerase chain reaction. METHODS: Four hundred Iranian individuals (age range: 17-42 years) were selected from 18 of Iran's 31 provinces. They were divided into four groups: (i) group A, persons with normal reactions to major life-event stressors; (ii) group B, persons with acute stress reactions to major life-event stressors; (iii) group C, persons with normal reactions to crises/catastrophes; and (iv) group D, persons with acute stress reactions to crises/catastrophes. Individuals were divided into groups by a senior psychiatrist based on an unstructured interview, the 21-item Depression Anxiety Stress Scale, and Connor-Davidson Resilience Scale. RESULTS: We found that the upregulation of DRD1, DRD2, DRD3, DRD4, DBH, DAT, and BDNF and the downregulation of serotonin transporter, monoamine oxidase A, and COMT are associated with stress resilience, which is modulated by dopaminergic and serotonergic pathways. CONCLUSIONS: Gene expression variations were not only correlated with stress resilience, but they were also associated with other psychological parameters including personality, depression, anxiety, and intelligence.

Gene expression study of mitochondrial complex I in schizophrenia and paranoid personality disorder.

OBJECTIVES: The aetiology and molecular mechanisms of schizophrenia (SCZ) and paranoid personality disorder (PPD) are not yet clarified. The present study aimed to assess the role of mitochondrial complex I and cell bioenergetic pathways in the aetiology and characteristics of SCZ and PPD. METHODS: mRNA levels of all genomic and mitochondrial genes which encode mitochondrial complex I subunits (44 genes) were assessed in blood in 634 SCZ, 340 PPD patients and 528 non-psychiatric subjects using quantitative real-time PCR, and associated comprehensive psychiatric, neurological and biochemical assessments. RESULTS: Significant expression changes of 18 genes in SCZ patients and 11 genes in PPD patients were detected in mitochondrial complex I. Most of these genes were novel candidate genes for SCZ and PPD. Several correlations between mRNA levels and severity of symptoms, drug response, deficits in attention, working memory, executive functions and brain activities were found. CONCLUSIONS: Deregulations of both core and supernumerary subunits of complex I are involved in the aetiology of SCZ and PPD. These deregulations have effects on brain activity as well as disorder characteristics.