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


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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    • "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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    ABSTRACT: Neurotransmission depends on synaptic vesicle (SV) exocytosis driven by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation of vesicular synaptobrevin/VAMP2 (Syb2). Exocytic fusion is followed by endocytic SV membrane retrieval and the high-fidelity reformation of SVs. Syb2 is the most abundant SV protein with 70 copies per SV, yet, one to three Syb2 molecules appear to be sufficient for basal exocytosis. Here we demonstrate that loss of the Syb2-specific endocytic adaptor AP180 causes a moderate activity-dependent reduction of vesicular Syb2 levels, defects in SV reformation, and a corresponding impairment of neurotransmission that lead to excitatory/inhibitory imbalance, epileptic seizures, and premature death. Further reduction of Syb2 levels in AP180(-/-)/Syb2(+/-) mice results in perinatal lethality, whereas Syb2(+/-) mice partially phenocopy loss of AP180, indicating that reduced vesicular Syb2 levels underlie the observed defects in neurotransmission. Thus, a large vesicular Syb2 pool maintained by AP180 is crucial to sustain efficient neurotransmission and SV reformation.
    Neuron 09/2015; DOI:10.1016/j.neuron.2015.08.034 · 15.05 Impact Factor
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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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    ABSTRACT: Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.
    Journal of the American Society for Experimental NeuroTherapeutics 07/2015; DOI:10.1007/s13311-015-0371-9 · 5.05 Impact Factor
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    • "In addition, important findings of increased numbers and size of microglia and excessive microglial activation has been shown in wide age range of individuals with ASD [12] [13] [14]. Genetic findings linking ASD to a number of pathways associated with neuronal synaptic function including the SHANK3 gene and mutations of other synaptic cell adhesion molecules, suggest that ASD may result, at least partially, from disruption of synapse formation or elimination [15] [16]. "
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    ABSTRACT: Recent studies of Autism Spectrum Disorders (ASD) highlight hyperactivity of the immune system, irregular neuronal growth and increased size and number of microglia. Though the small sample size in many of these studies limits extrapolation to all individuals with ASD, there is mounting evidence of both immune and nervous system related pathogenesis in at least a subset of patients with ASD. Given the disturbing rise in incidence rates for ASD, and the fact that no pharmacological therapy for ASD has been approved by the Food and Drug Administration (FDA), there is an urgent need for new therapeutic options. Research in the therapeutic effects of mesenchymal stem cells (MSC) for other immunological and neurological conditions has shown promising results in preclinical and even clinical studies. MSC have demonstrated the ability to suppress the immune system and to promote neurogenesis with a promising safety profile. The working hypothesis of this paper is that the potentially synergistic ability of MSC to modulate a hyperactive immune system and its ability to promote neurogenesis make it an attractive potential therapeutic option specifically for ASD. Theoretical mechanisms of action will be suggested, but further research is necessary to support these hypothetical pathways. The choice of tissue source, type of cell, and most appropriate ages for therapeutic intervention remain open questions for further consideration. Concern over poor regulatory control of stem cell studies or treatment, and the unique ethical challenges that each child with ASD presents, demands that future research be conducted with particular caution before widespread use of the proposed therapeutic intervention is implemented.
    Medical Hypotheses 12/2014; 84(3). DOI:10.1016/j.mehy.2014.12.016 · 1.07 Impact Factor
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