1. Babinska K, Bucova M, Durmanova V, Lakatosova S, Janosikova D, Bakos J, Hlavata A, Ostatnikova D. {{Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism}}. {Physiol Res};2015 (Feb 10);63 Suppl 4:S613-618.
Autism is a disorder of neural development characterized by impairments in communication, social interaction, restricted interests and repetitive behavior. The etiology of autism is poorly understood, the evidence indicates that inflammation may play a key role. In autism a high prevalence of gastrointestinal disturbances is reported, that are linked to a low-grade chronic inflammation of the intestinal mucosa. High mobility group box 1 protein (HMGB1) is an intranuclear protein that can be passively released from necrotic cells or actively secreted under inflammatory conditions as alarmin or late proinflammatory cytokine. The objective of this study was to measure plasma levels of HMGB1 in individuals with autism and to analyze their association with gastrointestinal symptoms. The study involved 31 subjects with low-functioning autistic disorder aged 2-22 years and 16 healthy controls. Plasma HMGB1 levels were significantly higher in individuals with autism than in controls (13.8+/-11.7 ng/ml vs. 7.90+/-4.0 ng/ml, p<0.02). In subjects with plasma HMGB1 levels higher than 11 ng/ml severe forms of GI disorders were more prevalent (83.3 %) than in subjects with lower levels (38.9 %, p<0.04). Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms.
2. Dhossche DM, van der Steen LF, Shettar SM. {{[Catatonia in autism spectrum disorders: Review and case-report]}}. {Tijdschr Psychiatr};2015;57(2):89-93.
BACKGROUND: Catatonia develops in children, adolescents, and adults with autism spectrum disorders.<br/> AIM: To review catatonia in autism spectrum disorders.<br/> METHOD: A case-report is presented and discussed.<br/> RESULTS: Catatonia is a comorbid syndrome occurring in 12-17% of selected groups of adolescents and young adults with autism spectrum disorders who have been referred for specialised care or admitted to hospital. Clinical experience and case-reports indicate that benzodiazepines and electroconvulsive therapy can be used safely and effectively in both the treatment in acute cases and maintenance treatments for catatonia patients with autism spectrum disorders.<br/> CONCLUSION: Catatonia is a recognisable and treatable syndrome in children and adolescents with autism spectrum disorders.
3. Kim SY, Choi US, Park SY, Oh SH, Yoon HW, Koh YJ, Im WY, Park JI, Song DH, Cheon KA, Lee CU. {{Abnormal activation of the social brain network in children with autism spectrum disorder: an FMRI study}}. {Psychiatry Investig};2015 (Jan);12(1):37-45.
OBJECTIVE: The aim of this study is to investigate abnormal findings of social brain network in Korean children with autism spectrum disorder (ASD) compared with typically developing children (TDC). METHODS: Functional magnetic resonance imaging (fMRI) was performed to examine brain activations during the processing of emotional faces (happy, fearful, and neutral) in 17 children with ASD, 24 TDC. RESULTS: When emotional face stimuli were given to children with ASD, various areas of the social brain relevant to social cognition showed reduced activation. Specifically, ASD children exhibited less activation in the right amygdala (AMY), right superior temporal sulcus (STS) and right inferior frontal gyrus (IFG) than TDC group when fearful faces were shown. Activation of left insular cortex and right IFG in response to happy faces was less in the ASD group. Similar findings were also found in left superior insular gyrus and right insula in case of neutral stimulation. CONCLUSION: These findings suggest that children with ASD have different processing of social and emotional experience at the neural level. In other words, the deficit of social cognition in ASD could be explained by the deterioration of the capacity for visual analysis of emotional faces, the subsequent inner imitation through mirror neuron system (MNS), and the ability to transmit it to the limbic system and to process the transmitted emotion.
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4. Lukose R, Beebe K, Kulesza RJ, Jr. {{Organization of the human superior olivary complex in 15q duplication syndromes and autism spectrum disorders}}. {Neuroscience};2015 (Feb 12);286:216-230.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a number of behavioral and social features. Although the etiology of most cases of ASD is idiopathic, a significant number of cases can be attributed to genetic causes, such as chromosome 15q duplications [dup(15q)]. Recent neuropathological investigations have provided evidence for distinct patterns of heterotopias and dysplasias in ASD and subjects with both ASD and dup(15q). Individuals with ASD characteristically have hearing difficulties and we have previously demonstrated significant and consistent hypoplasia in a number of auditory brainstem nuclei in subjects with ASD. Herein, we compare results from a morphometric investigation of auditory brainstem nuclei in subjects with ASD, dup(15q) and controls. Our observations in subjects with ASD support our previous reports. However, in subjects with dup(15q), we find significantly fewer neurons and in many nuclei, neurons were significantly smaller than in ASD subjects. Finally, we find a notably higher incidence of ectopic neurons in dup(15q). These results suggest that in the brainstem, these neuropathological conditions may evolve from some of the same developmental errors but are distinguished on microscopic features.
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5. Provenzano G, Pangrazzi L, Poli A, Sgado P, Berardi N, Bozzi Y. {{Reduced phosphorylation of synapsin I in the hippocampus of Engrailed-2 knockout mice, a model for autism spectrum disorders}}. {Neuroscience};2015 (Feb 12);286:122-130.
Mice lacking the homeodomain transcription factor Engrailed-2 (En2(-/-) mice) are a well-characterized model for autism spectrum disorders (ASD). En2(-/-) mice present molecular, neuropathological and behavioral deficits related to ASD, including down-regulation of ASD-associated genes, cerebellar hypoplasia, interneuron loss, enhanced seizure susceptibility, decreased sociability and impaired cognition. Specifically, impaired spatial learning in the Morris water maze (MWM) is associated with reduced expression of neurofibromin and increased phosphorylation of extracellular-regulated kinase (ERK) in the hippocampus of En2(-/-) adult mice. In the attempt to better understand the molecular cascades underlying neurofibromin-dependent cognitive deficits in En2 mutant mice, we investigated the expression and phosphorylation of synapsin I (SynI; a major target of neurofibromin-dependent signaling) in the hippocampus of wild-type (WT) and En2(-/-) mice before and after MWM. Here we show that SynI mRNA and protein levels are down-regulated in the hippocampus of naive and MWM-treated En2(-/-) mice, as compared to WT controls. This down-regulation is paralleled by reduced levels of SynI phosphorylation at Ser549 and Ser553 residues in the hilus of mutant mice, before and after MWM. These data indicate that in En2(-/-) hippocampus, neurofibromin-dependent pathways converging on SynI phosphorylation might underlie hippocampal-dependent learning deficits observed in En2(-/-) mice.
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6. Theoharides TC, Athanassiou M, Panagiotidou S, Doyle R. {{Dysregulated brain immunity and neurotrophin signaling in Rett syndrome and autism spectrum disorders}}. {J Neuroimmunol};2015 (Feb 15);279C:33-38.
Rett syndrome is a neurodevelopmental disorder, which occurs in about 1:15,000 females and presents with neurologic and communication defects. It is transmitted as an X-linked dominant linked to mutations of the methyl-CpG-binding protein (MeCP2), a gene transcription suppressor, but its definitive pathogenesis is unknown thus hindering development of effective treatments. Almost half of children with Rett syndrome also have behavioral symptoms consistent with those of autism spectrum disorders (ASDs). PubMed was searched (2005-2014) using the terms: allergy, atopy, brain, brain-derived neurotrophic factor (BDNF), corticotropin-releasing hormone (CRH), cytokines, gene mutations, inflammation, mast cells (MCs), microglia, mitochondria, neurotensin (NT), neurotrophins, seizures, stress, and treatment. There are a number of intriguing differences and similarities between Rett syndrome and ASDs. Rett syndrome occurs in females, while ASDs more often in males, and the former has neurologic disabilities unlike ASDs. There is evidence of dysregulated immune system early in life in both conditions. Lack of microglial phagocytosis and decreased levels of BDNF appear to distinguish Rett syndrome from ASDs, in which there is instead microglia activation and/or proliferation and possibly defective BDNF signaling. Moreover, brain mast cell (MC) activation and focal inflammation may be more prominent in ASDs than Rett syndrome. The flavonoid luteolin blocks microglia and MC activation, provides BDNF-like activity, reverses Rett phenotype in mouse models, and has a significant benefit in children with ASDs. Appropriate formulations of luteolin or other natural molecules may be useful in the treatment of Rett syndrome.
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7. Weston B, Fogal B, Cook D, Dhurjati P. {{An agent-based modeling framework for evaluating hypotheses on risks for developing autism: Effects of the gut microbial environment}}. {Med Hypotheses};2015 (Jan 28)
The number of cases diagnosed with Autism Spectrum Disorders is rising at an alarming rate with the Centers for Disease Control estimating the 2014 incidence rate as 1 in 68. Recently, it has been hypothesized that gut bacteria may contribute to the development of autism. Specifically, the relative balances between the inflammatory microbes clostridia and desulfovibrio and the anti-inflammatory microbe bifidobacteria may become destabilized prior to autism development. The imbalance leads to a leaky gut, characterized by a more porous epithelial membrane resulting in microbial toxin release into the blood, which may contribute to brain inflammation and autism development. To test how changes in population dynamics of the gut microbiome may lead to the imbalanced microbial populations associated with autism patients, we constructed a novel agent-based model of clostridia, desulfovibrio, and bifidobacteria population interactions in the gut. The model demonstrates how changing physiological conditions in the gut can affect the population dynamics of the microbiome. Simulations using our agent-based model indicate that despite large perturbations to initial levels of bacteria, the populations robustly achieve a single steady-state given similar gut conditions. These simulation results suggests that disturbance such as a prebiotic or antibiotic treatment may only transiently affect the gut microbiome. However, sustained prebiotic treatments may correct low population counts of bifidobacteria. Furthermore, our simulations suggest that clostridia growth rate is a key determinant of risk of autism development. Treatment of high-risk infants with supra-physiological levels of lysozymes may suppress clostridia growth rate, resulting in a steep decrease in the clostridia population and therefore reduced risk of autism development.
