The critical role of ASD-related gene CNTNAP3 in regulating synaptic development and social behavior in mice.

Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.

MicroRNA-197 controls ADAM10 expression to mediate MeCP2's role in the differentiation of neuronal progenitors.

Duplication of MECP2 (Methyl-CpG-binding protein 2) causes severe mental illness called MECP2 duplication syndrome (MDS), yet the underlying mechanism remains elusive. Here we show, in Tg(MECP2) transgenic mouse brain or cultured neural progenitor cells (NPCs), that elevated MeCP2 expression promotes NPC differentiation into neurons. Ectopic expression of MeCP2 inhibits ADAM10 and thus the NOTCH pathway during NPC differentiation. In human cells, this downregulation on ADAM10 was mediated by miRNA-197, which is upregulated by MeCP2. Surprisingly, miR-197 binds to the ADAM10 3'-UTR via its 3' side, not the canonical seed sequence on the 5' side. In mouse cells, a noncoding RNA Gm28836 is used to replace the function of miR-197 between MeCP2 and ADAM10. Similar to MeCP2, overexpressing miR-197 also promotes NPCs differentiation into neurons. Interestingly, three rare missense mutations (H371R, E394K, and G428S) in MECP2, which we identified in a Han Chinese autism spectrum disorders (ASD) cohort showed loss-of-function effects in NPC differentiation assay. These mutations cannot upregulate miR-197. Overexpressing miR-197 together with these MeCP2 mutations could rescue the downregulation on ADAM10. Not only the inhibitor of miR-197 could reverse the effect of overexpressed MeCP2 on NPCs differentiation, but also overexpression of miR-197 could reverse the NPCs differentiation defects caused by MECP2 mutations. Our results revealed that a regulatory axis involving MeCP2, miR-197, ADAM10, and NOTCH signaling is critical for NPC differentiation, which is affected by both MeCP2 duplication and mutation.

Suspiciousness in young minds: Convergent evidence from non-clinical, clinical and community twin samples.

BACKGROUND: We validated the Social Mistrust Scale (SMS) and utilized it to examine the structure, prevalence, and heritability of social mistrust in a large sample of Chinese children and adolescents. METHODS: In Study 1, a large sample of healthy twins (N=2094) aged 8 to 14years (M=10.27years, SD=2) completed the SMS. Structural equation modeling (SEM) was conducted to assess the structure of the SMS and to estimate the heritability of social mistrust in a sub-sample of twins (n=756 pairs). In Study 2, 32 adolescents with childhood-onset schizophrenia were compared with 34 healthy controls on levels of suspiciousness and clinical symptoms to examine the associations between the SMS and the Positive and Negative Syndrome Scale (PANSS). RESULTS: We found a three-factor structure for social mistrust (home, school, and general mistrust). Social mistrust was found to be moderately - heritable (19%-40%), with mistrust at home most strongly influenced by genetic factors. Compared with 11.76% of the healthy controls, 56.25% of the adolescents with early-onset schizophrenia exhibited very high levels of social mistrust on all three subscales of the SMS. The SMS exhibited good discriminant validity in distinguishing adolescents with childhood-onset schizophrenia from healthy controls and showed associations with a broad range of symptoms assessed by the PANSS. CONCLUSIONS: Social mistrust assessed by the SMS may be heritable. The SMS demonstrates good discriminant validity with clinical diagnoses of schizophrenia. However, it seems to be correlated with multiple aspects of psychopathology in the schizophrenia group, rather than being specific to delusional ideation/paranoia.

Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation.

BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders.

Relationships between behavioral symptoms of non-medicated Chinese children with attention deficit hyperactivity disorder and parenting stress: Comparison of different subtypes and comorbidities.

INTRODUCTION: To identify the characteristics of behavior problems among children with attention deficit hyperactivity disorder (ADHD) and their relation with parenting stress. METHODS: The Conners Parent Symptom Questionnaire (PSQ) and Parenting Stress Index (PSI) were used to assess the symptoms and parenting stress of 132 non-medicated children with ADHD as compared with 88 healthy controls. RESULTS: Every PSQ factor of ADHD children was higher than in the control group; children with the combined subtype of ADHD had the highest scores in conduct and learning problems, impulsivity/hyperactivity, and overall hyperactivity index; the PSI total stress, child domain, and parent domain scores were all higher in the ADHD group than in the control group; children with the combined subtype of ADHD had the highest score in the competence subscale of the parent domain, whereas the PSI total stress score of parents of children with ADHD and comorbid oppositional defiant disorder (ODD) was higher than that of parents of children with only ADHD. The PSI total stress score was positively correlated with all PSQ factor scores. The PSQ factors of conduct problems and learning problems were found to be significant predictors in a regression analysis. DISCUSSION: The children with ADHD exhibited abnormal parenting stress compared with healthy controls, which was much more pronounced when the children had comorbid ODD. Furthermore, parenting stress was related with the severity of ADHD symptoms, suggesting that children with the combined subtype of ADHD require particular attention in the future.

Decreased prefrontal lobe interhemispheric functional connectivity in adolescents with internet gaming disorder: a primary study using resting-state FMRI.

PURPOSES: Recent neuroimaging studies have shown that people with Internet gaming disorder (IGD) have structural and functional abnormalities in specific brain areas and connections. However, little is known about the alterations of the interhemispheric resting-state functional connectivity (rsFC) in participants with IGD. In the present study, we used a newly developed voxel-mirrored homotopic connectivity (VMHC) method to investigate the interhemispheric rsFC of the whole brain in participants with IGD. METHODS: We compared interhemispheric rsFC between 17 participants with IGD and 24 healthy controls, group-matched on age, gender, and education status. All participants were provided written informed consent. Resting-state functional and structural magnetic resonance images were acquired for all participants. The rsFC between bilateral homotopic voxels was calculated. Regions showing abnormal VMHC in IGD participants were adopted as regions of interest for correlation analyses. RESULTS: Compared to healthy controls, IGD participants showed decreased VMHC between the left and right superior frontal gyrus (orbital part), inferior frontal gyrus (orbital part), middle frontal gyrus and superior frontal gyrus. Further analyses showed Chen Internet Addiction Scale (CIAS)-related VMHC in superior frontal gyrus (orbital part) and CIAS (r = -0.55, p = 0.02, uncorrected). CONCLUSIONS: Our findings implicate the important role of altered interhemispheric rsFC in the bilateral prefrontal lobe in the neuropathological mechanism of IGD, and provide further supportive evidence for the reclassification of IGD as a behavioral addiction.

Parent Ratings of ADHD Symptoms in Chinese Urban Schoolchildren: Assessment With the Chinese ADHD Rating Scale-IV: Home Version.

OBJECTIVE: The objective of this study was to assess the psychometric properties of the Chinese ADHD Rating Scale-IV (ADHD RS-IV): Home Version and to explore parent ratings of ADHD symptoms in a large sample of urban schoolchildren in China. METHOD: Parents of a representative sample of 1,616 schoolchildren (aged 6-17) in 12 Chinese cities completed the ADHD RS-IV: Home Version. RESULTS: The Chinese ADHD RS-IV: Home Version demonstrated satisfactory internal consistency, test-retest reliability, parent-teacher correlation, discriminant validity, and convergent validity. Factor analysis revealed the DSM-IV two-factor model with "inattention" and "hyperactivity-impulsivity" dimensions, accounting for equal variances. Parent ratings revealed lower/similar scores for Chinese schoolchildren compared with the U.S. CONCLUSION: The ADHD RS-IV: Home Version is a reliable and valid ADHD rating scale in China. The factor structure is similar but not identical to the U.S. STUDY: Normative data reveal cultural differences in some aspects of the parent ratings of ADHD.

Trait impulsivity and impaired prefrontal impulse inhibition function in adolescents with internet gaming addiction revealed by a Go/No-Go fMRI study.

BACKGROUND: Recent studies suggest that Internet gaming addiction (IGA) is an impulse disorder, or is at least related to impulse control disorders. In the present study, we hypothesized that different facets of trait impulsivity may be specifically linked to the brain regions with impaired impulse inhibition function in IGA adolescents. METHODS: Seventeen adolescents with IGA and seventeen healthy controls were scanned during performance of a response-inhibition Go/No-Go task using a 3.0 T MRI scanner. The Barratt Impulsiveness Scale (BIS)-11 was used to assess impulsivity. RESULTS: There were no differences in the behavioral performance on the Go/No-Go task between the groups. However, the IGA group was significantly hyperactive during No-Go trials in the left superior medial frontal gyrus, right anterior cingulate cortex, right superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left precuneus and cuneus. Further, the bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right superior parietal lobule were significantly hypoactive during No-Go trials. Activation of the left superior medial frontal gyrus was positively associated with BIS-11 and Chen Internet Addiction Scale (CIAS) total score across IGA participants. CONCLUSIONS: Our data suggest that the prefrontal cortex may be involved in the circuit modulating impulsivity, while its impaired function may relate to high impulsivity in adolescents with IGA, which may contribute directly to the Internet addiction process.

Brief report: effects of solution-focused brief therapy group-work on promoting post-traumatic growth of mothers who have a child with ASD.

The study evaluated the impact of solution-focused brief therapy (SFBT) group-work on the post-traumatic growth (PTG) of mothers who have a child with ASD. A quasi-experimental design was used in which 43 mothers participated. 18 mothers in 2 SFBT groups (n = 9 in each group) received a 6-session SFBT group therapy while 25 mothers in a control group received no treatment. The Post-traumatic Growth Inventory was used to measure the PTG levels of the participants at baseline, post-treatment and 6-month follow-up assessments. Mothers who attended SFBT group-work reported higher PTG scores both at post-treatment (t = 4.065, p = .001) and 6-month follow-up (t = 2.980, p = .006) assessments. Further investigations to prove whether SFBT in groups can increase the positivity of clients would promote the use of SFBT.