1. Al-Ayadhi LY, Mostafa GA. {{Increased serum osteopontin levels in autistic children: Relation to the disease severity}}. {Brain Behav Immun};2011 (Apr 18)
Autoimmunity to brain may play an etiopathogenic role in autism. Osteopontin is a pro-inflammatory cytokine that has been shown to play an important role in various autoimmune neuroinflammatory diseases. Osteopontin induces IL-17 production by T-helper 17 lymphocytes, the key players in the pathogenesis of autoimmune disorders. Anti-osteopontin treatment reduces the clinical severity of some autoimmune neuroinflammatory diseases by reducing IL-17 production. We are the first to measure serum osteopontin levels, by ELISA, in 42 autistic children in comparison to 42 healthy-matched children. The relationship between serum osteopontin levels and the severity of autism which was assessed by using the Childhood Autism Rating Scale (CARS), was also studied. Autistic children had significantly higher serum osteopontin levels than healthy controls (P<0.001). Increased serum osteopontin levels were found in 89.5% (34/42) of autistic children. Children with severe autism had significantly higher serum osteopontin levels than patients with mild to moderate autism (P=0.02). Moreover, serum osteopontin levels of autistic patients had significant positive correlations with CARS (P=0.007). In conclusions, serum osteopontin levels were increased in many autistic children and they were significantly correlated to the severity of autism. Further wide-scale studies are warranted to shed light on the etiopathogenic role of osteopontin in autism and to investigate its relation to IL-17 and brain-specific auto-antibodies, which are indicators of autoimmunity, in these patients. The therapeutic role of anti-osteopontin antibodies in amelioration of autistic manifestations should also be studied.
2. Anney RJ, Kenny EM, O’Dushlaine C, Yaspan BL, Parkhomenka E, Buxbaum JD, Sutcliffe J, Gill M, Gallagher L, Bailey AJ, Fernandez BA, Szatmari P, Scherer SW, Patterson A, Marshall CR, Pinto D, Vincent JB, Fombonne E, Betancur C, Delorme R, Leboyer M, Bourgeron T, Mantoulan C, Roge B, Tauber M, Freitag CM, Poustka F, Duketis E, Klauck SM, Poustka A, Papanikolaou K, Tsiantis J, Anney R, Bolshakova N, Brennan S, Hughes G, McGrath J, Merikangas A, Ennis S, Green A, Casey JP, Conroy JM, Regan R, Shah N, Maestrini E, Bacchelli E, Minopoli F, Stoppioni V, Battaglia A, Igliozzi R, Parrini B, Tancredi R, Oliveira G, Almeida J, Duque F, Vicente A, Correia C, Magalhaes TR, Gillberg C, Nygren G, Jonge MD, Van Engeland H, Vorstman JA, Wittemeyer K, Baird G, Bolton PF, Rutter ML, Green J, Lamb JA, Pickles A, Parr JR, Couteur AL, Berney T, McConachie H, Wallace S, Coutanche M, Foley S, White K, Monaco AP, Holt R, Farrar P, Pagnamenta AT, Mirza GK, Ragoussis J, Sousa I, Sykes N, Wing K, Hallmayer J, Cantor RM, Nelson SF, Geschwind DH, Abrahams BS, Volkmar F, Pericak-Vance MA, Cuccaro ML, Gilbert J, Cook EH, Guter SJ, Jacob S, Nurnberger Jr JI, McDougle CJ, Posey DJ, Lord C, Corsello C, Hus V, Kolevzon A, Soorya L, Parkhomenko E, Leventhal BL, Dawson G, Vieland VJ, Hakonarson H, Glessner JT, Kim C, Wang K, Schellenberg GD, Devlin B, Klei L, Minshew N, Sutcliffe JS, Haines JL, Lund SC, Thomson S, Coon H, Miller J, McMahon WM, Munson J, Estes A, Wijsman EM. {{Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders}}. {Eur J Hum Genet};2011 (Apr 27)
Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by O’Dushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.European Journal of Human Genetics advance online publication, 27 April 2011; doi:10.1038/ejhg.2011.75.
3. Bolte S. {{[Psychobiosocial interventions for autism.]}}. {Nervenarzt};2011 (Apr 28)
A multitude of interventions is offered for the treatment of autism spectrum disorders (ASD). However, only few have demonstrated scientific evidence, and even the evaluated methods need further examination of their mechanisms and scope. This article provides a brief summary of the premises and principles of successful psychobiosocial ASD intervention. ABA, TEACCH, PECS, social skills and cognitive training are described as examples for established approaches to ASD. Training of mu-suppression using neurofeedback and reanimation of the fusiform gyrus and amygdala using computer-aided facial affect recognition training are introduced as neurobiologically based ASD interventions.
4. Ghanizadeh A. {{Gold implants and increased expression of metallothionein-I/II as a novel hypothesized therapeutic approach for autism}}. {Toxicology};2011 (Apr 28);283(1):63-64.
5. Peca J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, Lascola CD, Fu Z, Feng G. {{Shank3 mutant mice display autistic-like behaviours and striatal dysfunction}}. {Nature};2011 (Apr 28);472(7344):437-442.
Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan-McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice.
6. Weng SM, McLeod F, Bailey ME, Cobb SR. {{Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal}}. {Neuroscience};2011 (Apr 28);180:314-321.
Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X-linked gene, MECP2, has a phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype. One of the consequences of MeCP2 absence in the brain is altered functional and structural plasticity. We aimed to characterize synaptic effects related to plasticity in the hippocampus further and establish whether plasticity defects are amenable to pharmacological reversal. Using male mice in which Mecp2 expression was prevented by a stop cassette, we assessed synaptic plasticity in area CA1 at different phenotypic stages, scoring the mice weekly for overt RTT-like signs. Strongly symptomatic Mecp2(stop/y) mice displayed reduced long-term potentiation (LTP, 40.2+/-1.6% of wild-type), post-tetanic potentiation (PTP, 45+/-18.8% of wild-type) and paired-pulse facilitation (PPF, 78+/-0.1% of wild type) (all P<0.05), the impairment increasing with symptom severity score. These plasticity impairments were absent in presymptomatic mice. Repeated high frequency stimulation revealed pronounced LTP saturation in symptomatic Mecp2(stop/y) mice, suggesting an LTP ‘ceiling’ effect. Bath application of the weak NMDA receptor blocker memantine (1 muM) resulted in partial restoration of a short-term plasticity component. These data support that idea that progressive functional synaptic impairment is a key feature in the RTT brain and demonstrate the potential for the pharmacological restoration of plasticity function.
7. Wills S, Rossi CC, Bennett J, Martinez-Cerdeno V, Ashwood P, Amaral DG, Van de Water J. {{Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism}}. {Mol Autism};2011 (Apr 26);2(1):5.
ABSTRACT: BACKGROUND: Autism is a neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and nonverbal communication, with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes for autism are currently unclear. In a previous study, we determined that 21% of children with autism had plasma autoantibodies that were immunoreactive with a population of neurons in the cerebellum that appeared to be Golgi cells, a GABAergic interneuron. METHODS: We have now extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double labeling studies, that included one of the calcium binding proteins that are commonly co-localized in GABAergic neurons (calbindin, paralbumin, or calretinin), were also carried out to determine which GABAergic neurons were immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven subjects with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from murine adult males were similarly examined. RESULTS: In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double labeling sections with plasma and with antibodies directed against gamma-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was co-labeled in several of the autoantibody labeled cells while parvalbumin co-labeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain. CONCLUSIONS: These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a sub-population of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.
