1. Gatto CL, Broadie K. {{Fragile X mental retardation protein is required for programmed cell death and clearance of developmentally-transient peptidergic neurons}}. {Dev Biol};2011 (May 10)

Fragile X syndrome (FXS), caused by loss of fragile X mental retardation 1 (FMR1) gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 product (FMRP) is an RNA-binding protein best established to function in activity-dependent modulation of synaptic connections. In the Drosophila FXS disease model, loss of functionally-conserved dFMRP causes synaptic overgrowth and overelaboration in pigment dispersing factor (PDF) peptidergic neurons in the adult brain. Here, we identify a very different component of PDF neuron misregulation in dfmr1 mutants: the aberrant retention of normally developmentally-transient PDF tritocerebral (PDF-TRI) neurons. In wild-type animals, PDF-TRI neurons in the central brain undergo programmed cell death and complete, processive clearance within days of eclosion. In the absence of dFMRP, a defective apoptotic program leads to constitutive maintenance of these peptidergic neurons. We tested whether this apoptotic defect is circuit-specific by examining crustacean cardioactive peptide (CCAP) and bursicon circuits, which are similarly developmentally-transient and normally eliminated immediately post-eclosion. In dfmr1 null mutants, CCAP/bursicon neurons also exhibit significantly delayed clearance dynamics, but are subsequently eliminated from the nervous system, in contrast to the fully persistent PDF-TRI neurons. Thus, the requirement of dFMRP for the retention of transitory peptidergic neurons shows evident circuit specificity. The novel defect of impaired apoptosis and aberrant neuron persistence in the Drosophila FXS model suggests an entirely new level of « pruning » dysfunction may contribute to the FXS disease state.

2. Green SA, Carter AS. {{Predictors and Course of Daily Living Skills Development in Toddlers with Autism Spectrum Disorders}}. {J Autism Dev Disord};2011 (May 20)

Self-sufficiency is central to child and family well-being. This report focuses on predictors of adaptive daily living skills (DLS) development in young children with ASD and whether DLS gains predict decreases in parenting stress. Participants were 162 toddlers with ASD and their parents, assessed at 3 annual timepoints. Hierarchical Linear Models showed that age, DQ, and autism symptom severity uniquely predicted initial DLS and DLS growth. Child problem behaviors predicted initial DLS only. DLS was associated with change in parenting stress above and beyond DQ, autism symptom severity, and problem behaviors. Children with lower IQ and more severe symptoms showed slower DLS gains. Given its relation to parenting stress, DLS are an important intervention target in young children with ASD.

3. Kiliszek A, Kierzek R, Krzyzosiak WJ, Rypniewski W. {{Crystal structures of CGG RNA repeats with implications for fragile X-associated tremor ataxia syndrome}}. {Nucleic Acids Res};2011 (May 19)

The CGG repeats are present in the 5′-untranslated region (5′-UTR) of the fragile X mental retardation gene FMR1 and are associated with two diseases: fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X syndrome (FXS). FXTAS occurs when the number of repeats is 55-200 and FXS develops when the number exceeds 200. FXTAS is an RNA-mediated disease in which the expanded CGG tracts form stable structures and sequester important RNA binding proteins. We obtained and analysed three crystal structures of double-helical CGG repeats involving unmodified and 8-Br modified guanosine residues. Despite the presence of the non-canonical base pairs, the helices retain an A-form. In the G-G pairs one guanosine is always in the syn conformation, the other is anti. There are two hydrogen bonds between the Watson-Crick edge of G(anti) and the Hoogsteen edge of G(syn): O6.N1H and N7.N2H. The G(syn)-G(anti) pair shows affinity for binding ions in the major groove. G(syn) causes local unwinding of the helix, compensated elsewhere along the duplex. CGG helical structures appear relatively stable compared with CAG and CUG tracts. This could be an important factor in the RNA’s ligand binding affinity and specificity.

4. Klemmer P, Meredith RM, Holmgren CD, Klychnikov OI, Stahl-Zeng J, Loos M, van der Schors RC, Wortel J, Spijker S, Rotaru DC, Mansvelder HD, Smit AB, Li KW. {{Proteomics, ultrastructure and physiology of hippocampal synapses in a Fragile X Syndrome mouse model reveals pre-synaptic phenotype}}. {J Biol Chem};2011 (May 19)

Fragile X Syndrome (FXS), the most common form of hereditary mental retardation, is caused by a loss-of-function mutation of the Fmr1 gene, which encodes Fragile X Mental Retardation Protein (FMRP). FMRP affects dendritic protein synthesis thereby causing synaptic abnormalities. Here, we used a quantitative proteomics approach in an FXS mouse model to reveal changes in levels of hippocampal synapse proteins. Sixteen independent pools of Fmr1 knockout mice and wild type mice were analyzed using two sets of 8-plex iTRAQ experiments. Of 205 proteins quantified with at least 3 distinct peptides in both iTRAQ series, the abundance of 23 proteins differed between Fmr1 knock-out and wild type synapses with a false discovery rate (q-value) < 5%. Significant differences were confirmed by quantitative immuno-blotting. A group of proteins that are known to be involved in cell differentiation and neurite outgrowth were regulated, which included Basp1 and Gap43, known PKC substrates, and Cend1. Basp1 and Gap43 are predominantly expressed in growth cones and presynaptic terminals. In line with this, ultrastructural analysis in developing hippocampal FXS synapses revealed smaller active zones with corresponding postsynaptic densities and smaller pools of clustered vesicles, indicative of immature presynaptic maturation. A second group of proteins involved in synaptic vesicle release were up-regulated in the FXS mouse model. In accordance, paired-pulse- and short-term facilitation were significantly affected in these hippocampal synapses. Together, the altered regulation of presynaptically-expressed proteins, immature synaptic ultrastructure and compromised short-term plasticity point to presynaptic changes underlying glutamatergic transmission in FXS at this stage of development.

5. Spath MA, Feuth TB, Smits AP, Yntema HG, Braat DD, Thomas CM, van Kessel AG, Sherman SL, Allen EG. {{Predictors and risk model development for menopausal age in fragile X premutation carriers}}. {Genet Med};2011 (May 18)

PURPOSE:: Women who carry a fragile X mental retardation 1 premutation are at risk for fragile X-associated primary ovarian insufficiency and should be counseled for a potentially reduced fertility. Multiple factors can affect the age of onset and severity of fragile X-associated primary ovarian insufficiency. In this study, we assessed the predictive power of several factors with menopausal age, a surrogate measure of onset of fragile X-associated primary ovarian insufficiency. METHODS:: Genetic, environmental, and reproductive factors were analyzed by Cox proportional hazard models in 1068 women, 385 of fragile X families ascertained through the Nijmegen study and 683 of fragile X families or general population families ascertained through the Atlanta study. RESULTS:: The highest association with menopausal age among fragile X mental retardation 1 premutation carriers was found for risk index by CGG repeat size (hazard ratio, 1.43) and smoking (hazard ratio, 1.34). Women from the Nijmegen cohort showed an overall lower age at menopause onset, for which a correction was made. A prediction model based on these two parameters, mean menopausal age of first-degree relatives with the same mutation status and the correction for ascertainment site, estimated the probability of becoming postmenopausal for premutation carriers, with a margin of 7-10%. CONCLUSION:: We conclude that this model serves as a first step toward clinical application of fragile X-associated primary ovarian insufficiency prediction.

6. Wei H, Zou H, Sheikh A, Malik M, Dobkin C, Brown T, Li X. {{IL-6 is increased in the cerebellum of the autistic brain and alters neural cell adhesion, migration and synapse formation}}. {J Neuroinflammation};2011 (May 19);8(1):52.

ABSTRACT: BACKGROUND: Although the cellular mechanisms responsible for the pathogenesis of autism are not understood, a growing number of studies have suggested that localized inflammation of the central nervous system (CNS) may contribute to the development of autism. Recent evidence shows that IL-6 has a crucial role in the development and plasticity of CNS. METHODS: Immunohistochemistry studies were employed to detect the IL-6 expression in the cerebellum of study subjects. In vitro adenoviral gene delivery approach was used to over-express IL-6 in cultured cerebellar granule cells. Cell adhesion and migration assays, DiI labeling, TO-PRO-3 staining and Immunofluorescence were used to examine cell adhesion and migration, dendritic spine morphology, cell apoptosis and synaptic protein expression respectively. RESULTS: In this study, we found that IL-6 was significantly increased in the cerebellum of autistic subjects. We investigated how IL-6 affects neural cell development and function by transfecting cultured mouse cerebellar granule cells with an IL-6 viral expression vector. We demonstrated that IL-6 over-expression in granule cells caused impairments in granule cell adhesion and migration but had little effect on the formation of dendritic spines or granule cell apoptosis. However, IL-6 over-expression stimulated the formation of granule cell excitatory synapses, without affecting inhibitory synapses. CONCLUSIONS: Our results provide further evidence that aberrant IL-6 may be associated with autism. In addition, our results suggest that the elevated IL-6 in the autistic brain could alter neural cell adhesion, migration and also cause an imbalance of excitatory and inhibitory circuits. Thus, increased IL-6 expression may be partially responsible for the pathogenesis of autism.

7. Zou H, Yang K, Sheikh AM, Malik M, Wen G, Chadman KK, Yu Y, Brown WT, Li X. {{Association of up-regulated Ras/Raf/ERK1/2 signaling with autism}}. {Genes Brain Behav};2011 (May 19)

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, verbal communication and repetitive behaviors. BTBR mouse is currently used as a model for understanding mechanisms that may be responsible for the pathogenesis of autism. Growing evidence suggests that Ras/Raf/ERK1/2 signaling plays death-promoting apoptotic roles in neural cells. Recent studies demonstrated a possible association between neural cell death and autism. In addition, two studies reported that a deletion of a locus on chromosome 16, which includes the MAPK3 gene that encodes ERK1, is associated with autism. We thus hypothesized that Ras/Raf/ERK1/2 signaling could be abnormally regulated in the brain of BTBR mice that models autism. In this study, we show that expression of Ras protein was significantly elevated in frontal cortex and cerebellum of BTBR mice as compared with B6 mice. The phosphorylation of A-Raf, B-Raf and C-Raf were all significantly increased in frontal cortex of BTBR mice. However, only C-Raf phosphorylation was increased in cerebellum of BTBR mice. In addition, we further detected that the activities of both MEK1/2 and ERK1/2, which are the downstream kinases of Ras/Raf signaling, were significantly enhanced in the frontal cortex. We also detected that ERK1/2 is significantly up-expressed in frontal cortex of autistic subjects. Our results indicate that Ras/Raf/ERK1/2 signaling is up-regulated in the frontal cortex of BTBR mice that model autism. These findings, together with the enhanced ERK1/2 expression in autistic frontal cortex, imply that Ras/Raf/ERK1/2 signaling activities could be increased in autistic brain and involved in the pathogenesis of autism.