1. Bu Q, Wang A, Hamzah H, Waldman A, Jiang K, Dong Q, Li R, Kim J, Turner D, Chang Q. {{CREB Signaling Is Involved in Rett Syndrome Pathogenesis}}. {J Neurosci};2017 (Mar 29);37(13):3671-3685.
Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the MECP2 gene. To facilitate the study of cellular mechanisms in human cells, we established several human stem cell lines: human embryonic stem cell (hESC) line carrying the common T158M mutation (MECP2T158M/T158M ), hESC line expressing no MECP2 (MECP2-KO), congenic pair of wild-type and mutant RTT patient-specific induced pluripotent stem cell (iPSC) line carrying the V247fs mutation (V247fs-WT and V247fs-MT), and iPSC line in which the V247fs mutation was corrected by CRISPR/Cas9-based genome editing (V247fs-MT-correction). Detailed analyses of forebrain neurons differentiated from these human stem cell lines revealed genotype-dependent quantitative phenotypes in neurite growth, dendritic complexity, and mitochondrial function. At the molecular level, we found a significant reduction in the level of CREB and phosphorylated CREB in forebrain neurons differentiated from MECP2T158M/T158M , MECP2-KO, and V247fs-MT stem cell lines. Importantly, overexpression of CREB or pharmacological activation of CREB signaling in those forebrain neurons rescued the phenotypes in neurite growth, dendritic complexity, and mitochondrial function. Finally, pharmacological activation of CREB in the female Mecp2 heterozygous mice rescued several behavioral defects. Together, our study establishes a robust in vitro platform for consistent quantitative evaluation of genotype-dependent RTT phenotypes, reveals a previously unappreciated role of CREB signaling in RTT pathogenesis, and identifies a potential therapeutic target for RTT.SIGNIFICANCE STATEMENT Our study establishes a robust human stem cell-based platform for consistent quantitative evaluation of genotype-dependent Rett syndrome (RTT) phenotypes at the cellular level. By providing the first evidence that enhancing cAMP response element binding protein signaling can alleviate RTT phenotypes both in vitro and in vivo, we reveal a previously unappreciated role of cAMP response element binding protein signaling in RTT pathogenesis, and identify a potential therapeutic target for RTT.
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2. Dalwai S, Ahmed S, Udani V, Mundkur N, Kamath SS, MK CN. {{Consensus Statement of the Indian Academy of Pediatrics on Evaluation and Management of Autism Spectrum Disorder}}. {Indian Pediatr};2017 (Mar 29)
JUSTIFICATION: Autism Spectrum Disorder (ASD) is a clinically heterogenous condition with a wide range of etiological factors and causing significant public health burden. ASD poses a serious developmental disadvantage to the child in the form of poor schooling, social function and adult productivity. Thus, framing evidence-based national guidelines is a pressing need. PROCESS: The meeting on formulation of national consensus guidelines on neurodevelopmental disorders was organized by Indian Academy of Paediatrics in Mumbai on 18th and 19th December 2015. The invited experts included Pediatricians, Developmental Pediatricians, Psychiatrists, Remedial Educators, Pediatric Neurologists and Clinical Psychologists. The participants framed guidelines after extensive discussions. Thereafter, a committee was established to review the points discussed in the meeting. OBJECTIVE: To provide consensus guidelines on evaluation and management of ASD in children in India. RECOMMENDATIONS: Intervention should begin as early as possible. A definitive diagnosis is not necessary for commencing intervention. Intervention should target core features of autism i.e. deficits in social communication and interaction, and restricted repetitive patterns of behavior, activities and/or interests. Intervention should be specific, evidence-based, structured and appropriate to the developmental needs of the child. Management of children should be provided through interdisciplinary teams, coordinated by the Pediatrician. Management of co-morbidities is critical to effectiveness of treatment. Pharmacotherapy may be offered to children when there is a specific target symptom or co-morbid condition.
3. Mitra M. {{Postpartum Health of Women with Intellectual and Developmental Disabilities: A Call to Action}}. {J Womens Health (Larchmt)};2017 (Mar 29)
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4. Yang YJ, Allen T, Abdullahi SM, Pelphrey KA, Volkmar FR, Chapman SB. {{Brain responses to biological motion predict treatment outcome in young adults with autism receiving Virtual Reality Social Cognition Training: Preliminary findings}}. {Behav Res Ther};2017 (Mar 29);93:55-66.
Autism Spectrum Disorder (ASD) is characterized by remarkable heterogeneity in social, communication, and behavioral deficits, creating a major barrier in identifying effective treatments for a given individual with ASD. To facilitate precision medicine in ASD, we utilized a well-validated biological motion neuroimaging task to identify pretreatment biomarkers that can accurately forecast the response to an evidence-based behavioral treatment, Virtual Reality-Social Cognition Training (VR-SCT). In a preliminary sample of 17 young adults with high-functioning ASD, we identified neural predictors of change in emotion recognition after VR-SCT. The predictors were characterized by the pretreatment brain activations to biological vs. scrambled motion in the neural circuits that support (a) language comprehension and interpretation of incongruent auditory emotions and prosody, and (b) processing socio-emotional experience and interpersonal affective information, as well as emotional regulation. The predictive value of the findings for individual adults with ASD was supported by regression-based multivariate pattern analyses with cross validation. To our knowledge, this is the first pilot study that shows neuroimaging-based predictive biomarkers for treatment effectiveness in adults with ASD. The findings have potentially far-reaching implications for developing more precise and effective treatments for ASD.
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5. Zhao D, Mokhtari R, Pedrosa E, Birnbaum R, Zheng D, Lachman HM. {{Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress}}. {Mol Autism};2017;8:17.
BACKGROUND: Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial. METHODS: In the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2+/-; Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks). RESULTS: We found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks. CONCLUSIONS: These findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway.
