1. Brugha TS, McManus S, Smith J, Scott FJ, Meltzer H, Purdon S, Berney T, Tantam D, Robinson J, Radley J, Bankart J. {{Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community}}. {Psychol Med};2011 (Jul 29):1-10.
BACKGROUND: There are no tested methods for conducting epidemiological studies of autism spectrum disorders (ASDs) in adult general population samples. We tested the validity of the Autism Diagnostic Observation Schedule module-4 (ADOS-4) and the 20-item Autism-Spectrum Quotient (AQ-20).MethodRandomly sampled adults aged 16 years were interviewed throughout England in a general population multi-phase survey. The AQ-20 was self-completed by 7353 adults in phase 1. A random subset completed phase 2, ADOS-4 assessments (n=618); the probability of selection increased with AQ-20 score. In phase 3, informant-based Diagnostic Interview Schedule for Social and Communication Disorders (DISCO) and Autism Diagnostic Interview – Revised (ADI-R) developmental assessments were completed (n=56). Phase 1 and 2 data were presented as vignettes to six experienced clinicians (working in pairs). The probability of respondents having an ASD was compared across the three survey phases. RESULTS: There was moderate agreement between clinical consensus diagnoses and ADOS-4. A range of ADOS-4 caseness thresholds was identified by clinicians: 5+ to 13+ with greatest area under the curve (AUC) at 5+ (0.88). Modelling of the presence of ASD using 56 DISCO assessments suggested an ADOS-4 threshold in the range of 10+ to 13+ with the highest AUC at ADOS 10+ to 11+ (0.93-0.94). At ADOS 10+, the sensitivity was 1 [95% confidence interval (CI) 0.59-1.0] and the specificity 0.86 (95% CI 0.72-0.94). The AQ-20 was only a weak predictor of ADOS-4 cases. CONCLUSIONS: Clinically recommended ADOS-4 thresholds are also recommended for community cases: 7+ for subthreshold and 10+ for definite cases. Further work on adult population screening methods is needed.
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2. Deng PY, Sojka D, Klyachko VA. {{Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile x syndrome}}. {J Neurosci};2011 (Jul 27);31(30):10971-10982.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS.
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3. Gross C, Berry-Kravis EM, Bassell GJ. {{Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond}}. {Neuropsychopharmacology};2011 (Jul 27)
Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.Neuropsychopharmacology Reviews advance online publication, 27 July 2011; doi:10.1038/npp.2011.137.
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4. Halgren C, Kjaergaard S, Bak M, Hansen C, El-Schich Z, Anderson CM, Henriksen KF, Hjalgrim H, Kirchhoff M, Bijlsma EK, Nielsen M, den Hollander NS, Ruivenkamp CA, Isidor B, Le Caignec C, Zannolli R, Mucciolo M, Renieri A, Mari F, Anderlid BM, Andrieux J, Dieux A, Tommerup N, Bache I. {{Corpus Callosum Abnormalities, Mental Retardation, Speech Impairment, and Autism in Patients with Haploinsufficiency of ARID1B}}. {Clin Genet};2011 (Jul 29)
Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe mental retardation to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases but the underlying genetic cause remain unknown in the majority of cases. By next-generation mate pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced t(1;6)(p31;q25), agenesis of corpus callosum, mental retardation, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Q-PCR data revealed that a primer set proximal to the translocation showed increased expression of ARID1B while primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to 7 unpublished patients with various sized deletions encompassing ARID1B confirm that haploinsufficiency of ARID1B is associated with corpus callosum abnormalities, mental retardation, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of corpus callosum and in speech development in particular.
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5. Jyonouchi H, Geng L, Streck DL, Toruner GA. {{Children with autism spectrum disorders (ASD) who exhibit chronic gastrointestinal (GI) symptoms and marked fluctuation of behavioral symptoms exhibit distinct innate immune abnormalities and transcriptional profiles of peripheral blood (PB) monocytes}}. {J Neuroimmunol};2011 (Jul 29)
Innate/adaptive immune responses and transcript profiles of peripheral blood monocytes were studied in ASD children who exhibit fluctuating behavioral symptoms following infection and other immune insults (ASD/Inf, N=30). The ASD/Inf children with persistent gastrointestinal symptoms (ASD/Inf+GI, N=19), revealed less production of proinflammatory and counter-regulatory cytokines with stimuli of innate immunity and marked changes in transcript profiles of monocytes as compared to ASD/no-Inf (N=28) and normal (N=26) controls. This included a 4-5 fold up-regulation of chemokines (CCL2 and CCL7), consistent with the production of more CCL2 by ASD/Inf+GI cells. These results indicate dysregulated innate immune defense in the ASD/Inf+GI children, rendering them more vulnerable to common microbial infection/dysbiosis and possibly subsequent behavioral changes.
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6. Paluszkiewicz SM, Olmos-Serrano JL, Corbin JG, Huntsman MM. {{Impaired inhibitory control of cortical synchronization in fragile x syndrome}}. {J Neurophysiol};2011 (Jul 27)
Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. Here we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KOs. We demonstrate reduced activation of somatostatin (SOM)-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist DHPG in Fmr1 KOs, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KOs. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KOs. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.
