Article

A synaptic trek to autism

Human Genetics and Cognitive Functions, Institut Pasteur, 25 rue du Docteur Roux, 75015 Paris, France.
Current opinion in neurobiology (Impact Factor: 6.63). 07/2009; 19(2):231-4. DOI: 10.1016/j.conb.2009.06.003
Source: PubMed

ABSTRACT

Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD.

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    • "Both genes are reduced in patients with ASD relative to neurotypical controls and are associated with changes in DNA methylation and hydroxymethylation marks within the promoter region leading to MECP2-dependent repres- sion [158]. Imbalances in synaptic connectivity have also been posited as a mechanism underlying ASD pathogenesis [77, 159] and may provide a biological substrate for enhanced susceptibility to environmental factors [27, 77, 159]. The synaptic protein SH3 and multiple repeat domains 3, SHANK3, is a postsynaptic scaffolding protein of excitatory glutamatergic synapses. "
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    ABSTRACT: There is now compelling evidence that gene by environment interactions are important in the etiology of autism spectrum disorders (ASDs). However, the mechanisms by which environmental factors interact with genetic susceptibilities to confer individual risk for ASD remain a significant knowledge gap in the field. The epigenome, and in particular DNA methylation, is a critical gene expression regulatory mechanism in normal and pathogenic brain development. DNA methylation can be influenced by environmental factors such as diet, hormones, stress, drugs, or exposure to environmental chemicals, suggesting that environmental factors may contribute to adverse neurodevelopmental outcomes of relevance to ASD via effects on DNA methylation in the developing brain. In this review, we describe epidemiological and experimental evidence implicating altered DNA methylation as a potential mechanism by which environmental chemicals confer risk for ASD, using polychlorinated biphenyls (PCBs), lead, and bisphenol A (BPA) as examples. Understanding how environmental chemical exposures influence DNA methylation and how these epigenetic changes modulate the risk and/or severity of ASD will not only provide mechanistic insight regarding gene-environment interactions of relevance to ASD but may also suggest potential intervention strategies for these and potentially other neurodevelopmental disorders.
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    • "Hence, the number of releasable SVs at AP180-deficient synapses may be insufficient to sustain high-frequency neurotransmission. Interestingly, AP180 has been associated with psychotic bipolar disorder (Goes et al., 2012) and ASDs (Ben-David and Shifman, 2012), established ''synaptopathies'' (Bourgeron, 2009; Sü dhof, 2008; Zoghbi, 2003). In fact, excitatory/inhibitory imbalance not only underlies epilepsy but has also been implicated in mouse models for ASDs (Tabuchi et al., 2007). "
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    • "A set of genes involved in neurodevelopmental processes that mediate the formation, stabilization, and pruning of synapses have been consistently associated with autism-related phenotypes in animal models [126] [127] [128]. Neuroligins (NLGN) represent a significant part of this set, and indeed several genes of NLGN family have been associated with autism [129]. In a mouse model, autism-associated mutation in NLGN3 was found to be associated with deficits in social behaviour [130], and disrupted tonic eCB signalling [131]. "
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