Xiu Xu

Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2.

Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.

Strain-mediated electric-field control of exchange bias in a Co90Fe10/BiFeO3/SrRuO3/PMN-PT heterostructure

The electric-field (E-field) controlled exchange bias (EB) in a Co90Fe10/BiFeO3 (BFO)/SrRuO3/PMN-PT heterostructure has been investigated under different tensile strain states. The in-plane tensile strain of the BFO film is changed from +0.52% to +0.43% as a result of external E-field applied to the PMN-PT substrate. An obvious change of EB by the control of non-volatile strain has been observed. A magnetization reversal driven by E-field has been observed in the absence of magnetic field. Our results indicate that a reversible non-volatile E-field control of a ferromagnetic layer through strain modulated multiferroic BFO could be achieved at room temperature.

Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood.ResultsHere we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically.ConclusionsDeep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models.

Risk Factors for Autistic Regression Results of an Ambispective Cohort Study

A subgroup of children diagnosed with autism experience developmental regression featured by a loss of previously acquired abilities. The pathogeny of autistic regression is unknown, although many risk factors likely exist. To better characterize autistic regression and investigate the association between autistic regression and potential influencing factors in Chinese autistic children, we conducted an ambispective study with a cohort of 170 autistic subjects. Analyses by multiple logistic regression showed significant correlations between autistic regression and febrile seizures (OR = 3.53, 95% CI = 1.17-10.65, P = .025), as well as with a family history of neuropsychiatric disorders (OR = 3.62, 95% CI = 1.35-9.71, P = .011). This study suggests that febrile seizures and family history of neuropsychiatric disorders are correlated with autistic regression.

A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections

BackgroundAutistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism.Case presentationHere, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2-containing duplication (151,369,305 – 153,589,577) from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy.ConclusionsTo our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients.

Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism

Autism spectrum disorder (ASD) encompasses a complex set of developmental neurological disorders, characterized by deficits in social communication and excessive repetitive behaviors. In recent years, ASD is increasingly being considered as a disease of the synapse. One main type of genetic aberration leading to ASD is gene duplication, and several mouse models have been generated mimicking these mutations. Here, we studied the effects of MECP2 duplication and human chromosome 15q11-13 duplication on synaptic development and neural circuit wiring in the mouse sensory cortices. We showed that mice carrying MECP2 duplication had specific defects in spine pruning, while the 15q11-13 duplication mouse model had impaired spine formation. Our results demonstrate that spine pathology varies significantly between autism models and that distinct aspects of neural circuit development may be targeted in different ASD mutations. Our results further underscore the importance of gene dosage in normal development and function of the brain.

The autism-related gene SNRPN regulates cortical and spine development via controlling nuclear receptor Nr4a1.

The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene, encoding the RNA-associated SmN protein, duplications or deletions of which are strongly associated with neurodevelopmental disabilities. SNRPN-coding protein is highly expressed in the brain. However, the role of SNRPN protein in neural development remains largely unknown. Here we showed that the expression of SNRPN increased markedly during postnatal brain development. Overexpression or knockdown of SNRPN in cortical neurons impaired neurite outgrowth, neuron migration, and the distribution of dendritic spines. We found that SNRPN regulated the expression level of Nr4a1, a critical nuclear receptor during neural development, in cultured primary cortical neurons. The abnormal spine development caused by SNRPN overexpression could be fully rescued by Nr4a1 co-expression. Importantly, we found that either knockdown of Nr4a1 or 3, 3′- Diindolylmethane (DIM), an Nr4a1 antagonist, were able to rescue the effects of SNRPN knockdown on neurite outgrowth of embryonic cortical neurons, providing the potential therapeutic methods for SNRPN deletion disorders. We thus concluded that maintaining the proper level of SNRPN is critical in cortical neurodevelopment. Finally, Nr4a1 may serve as a potential drug target for SNRPN-related neurodevelopmental disabilities, including Prader-Willi syndrome (PWS) and autism spectrum disorders (ASDs).

Alterations in plasma cytokine levels in chinese children with autism spectrum disorder: Cytokine level changes in Chinese ASD children

Genetic alterations, together with environmental risk factors during infancy and childhood, contribute significantly to the etiology of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental condition characterized by impairments in social interaction and restricted, repetitive behaviors. Mounting evidence points to a critical contribution of immunological risk factors to the development of ASD. By affecting multiple neurodevelopmental processes, immune system dysfunction could act as a point of convergence between genetics and environmental factors in ASD. Previous studies have shown altered cytokine levels in individuals with ASD, but research in Asian populations are limited. Here, we measured the plasma levels of 11 candidate cytokines in ASD and typically developing (TD) children. The cohort included 41 TD children and 87 children with ASD, aged 1–6 years. We found that as compared to the TD group, children with ASD had higher plasma levels of Eotaxin, TGF‐β1 and TNF‐α. The increase in TGF‐β1 level was most significant in males, while the increase in Eotaxin was most significant in females. Eotaxin level negatively correlated with the social affect score (SA) in ADOS, while TNF‐α level positively correlated with total development quotient (DQ), measured using GMDS. These pilot findings suggest potentially important roles of Eotaxin, TGF‐β1 and TNF‐α in ASD in the Chinese population. Autism Res 2018, 11: 989–999.

Role of PUF60 gene in Verheij syndrome: a case report of the first Chinese Han patient with a de novo pathogenic variant and review of the literature

BackgroundVerheij syndrome is a rare microdeletion syndrome of chromosome 8q24.3 that harbors PUF60, SCRIB, and NRBP2 genes. Subsequently, loss of function mutations in PUF60 have been found in children with clinical features significantly overlapping with Verheij.Case presentationHere we present the first Chinese Han patient with a de novo nonsense variant (c.1357C > T, p.Gln453*) in PUF60 by clinical whole exome sequencing. The 5-year-old boy presents with dysmorphic facial features, intellectual disability, and growth retardation but without apparent cardiac, renal, ocular, and spinal anomalies.ConclusionsOur finding contributes to the understanding of the genotype and phenotype in PUF60 related disorder.

Improving the early screening procedure for autism spectrum disorder in young children: Experience from a community-based model in shanghai: Li et al./Community-based early screening for ASD in China

Most children with autism spectrum disorder (ASD) are not diagnosed until the age of 4, thus missing the opportunity for early intervention. The objective of this study was to investigate the feasibility of an early screening program for ASD applied during well‐child visits in a community‐based sample. The study lasted for 4 years and was divided into two stages. Stage I involved the implementation of the basic screening model in 2014. Toddlers received level 1 screening via section A of the Chinese‐validated version of the Checklist for Autism in Toddlers (CHAT‐23) during 18‐ and 24‐month well‐child visits in Xuhui District, Shanghai, China. Screen‐positive children were referred to receive section B of the CHAT‐23 for level 2 screening, and those still screen‐positive were referred to undergo diagnosis and evaluation. Stage II involved the implementation of the improved screening model from 2015 to 2017 with the following modifications: (a) an added observational component in level 1 screening; (b) telephone follow‐ups with the screen‐positive families; and (c) dissemination of information on ASD to families. The results showed that 42 of 22,247 screened children were diagnosed with ASD. The ASD diagnosis rates were 0.1% in Stage I and 0.21% in Stage II. The screen‐positive rate and the show rate of referral for level 1 screening increased by 76.92% and 58.43%, respectively, in Stage II compared to Stage I. Our results suggest that with appropriate logistic support, this two‐level screening model is feasible and effective for the early screening of ASD during well‐child visits. Autism Res 2018, 11: 1206–1217.