Levitt P, Campbell DB. The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J Clin Invest 119: 747-754

Vanderbilt Kennedy Center for Research on Human Development and Department of Pharmacology,Vanderbilt University Medical Center, Nashville, Tennessee, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 05/2009; 119(4):747-54. DOI: 10.1172/JCI37934
Source: PubMed


Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.

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Available from: Daniel Campbell, Jul 15, 2014
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    • "Unlike transgenic knockout mouse models, whose impaired sociability may be causally-related to diminished or absent expression of single major genes, the genetically-inbred Balb/c and BTBR T + Itpr3tf/J (BTBR) mouse models are particularly interesting models of ASD because their impaired sociability may reflect subtle epistatic interactions within a network of related genes, many of which may be normal polymorphisms (Cuscó et al., 2009; Levitt and Campbell, 2009). Syndromic forms of ASD due to the effects of single major genes (e.g. "
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    ABSTRACT: Tuberous Sclerosis Complex is one example of a syndromic form of autism spectrum disorder associated with disinhibited activity of mTORC1 in neurons (e.g., cerebellar Purkinje cells). mTORC1 is a complex protein possessing serine/threonine kinase activity and a key downstream molecule in a signaling cascade beginning at the cell surface with the transduction of neurotransmitters (e.g., glutamate and acetylcholine) and nerve growth factors (e.g., Brain-Derived Neurotrophic Factor). Interestingly, the severity of the intellectual disability in Tuberous Sclerosis Complex may relate more to this metabolic disturbance (i.e., overactivity of mTOR signaling) than the density of cortical tubers. Several recent reports showed that rapamycin, an inhibitor of mTORC1, improved sociability and other symptoms in mouse models of Tuberous Sclerosis Complex and autism spectrum disorder, consistent with mTORC1 overactivity playing an important pathogenic role. NMDA receptor activation may also dampen mTORC1 activity by at least two possible mechanisms: regulating intraneuronal accumulation of arginine and the phosphorylation status of a specific extracellular signal regulating kinase (i.e., ERK1/2), both of which are "drivers" of mTORC1 activity. Conceivably, the prosocial effects of targeting the NMDA receptor with agonists in mouse models of autism spectrum disorders result from their ability to dampen mTORC1 activity in neurons. Strategies for dampening mTORC1 overactivity by NMDA receptor activation may be preferred to its direct inhibition in chronic neurodevelopmental disorders, such as autism spectrum disorders. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2015; 60. DOI:10.1016/j.pnpbp.2015.02.009 · 3.69 Impact Factor
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    • "Our laboratory has demonstrated that plasma HGF and EGF (the ligands for MET and EGFR, respectively) are significantly decreased in autistic children,10,11 and in the data reported here, we have found that EGFR is increased. We also found in this study and previous studies that EGF and EGFR levels, but not HGF levels, correlate with symptom severity in autistic children.10,11 "
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    ABSTRACT: BACKGROUND One in 88 children in the US is thought to have one of the autism spectrum disorders (ASDs). ASDs are characterized by social impairments and communication problems. Growth factors and their receptors may play a role in the etiology of ASDs. Research has shown that epidermal growth factor receptor (EGFR) activation is associated with nerve cell development and repair. This study was designed to measure plasma levels of EGFR in autistic children and correlate these levels with its ligand, epidermal growth factor, other related putative biomarkers such as hepatocyte growth factor (HGF), the ligand for MET (MNNG HOS transforming gene) receptor, as well as the symptom severity of 19 different behavioral symptoms. SUBJECTS AND METHODS Plasma EGFR concentration was measured in 33 autistic children and 34 age- and gender-similar neurotypical controls, using an enzyme-linked immunosorbent assay. Plasma EGFR levels were compared to putative biomarkers known to be associated with EGFR and MET and severity levels of 19 autism-related symptoms. RESULTS We found plasma EGFR levels significantly higher in autistic children, when compared to neurotypical controls. EGFR levels correlated with HGF and high-mobility group protein B1 (HMGB1) levels, but not other tested putative biomarkers, and EGFR levels correlated significantly with severity of expressive language, conversational language, focus/attention, hyperactivity, eye contact, and sound sensitivity deficiencies. CONCLUSIONS These results suggest a relationship between increased plasma EGFR levels and designated symptom severity in autistic children. A strong correlation between plasma EGFR and HGF and HMGB1 suggests that increased EGFR levels may be associated with the HGF/Met signaling pathway, as well as inflammation.
    Journal of Central Nervous System Disease 09/2014; 6:79-83. DOI:10.4137/JCNSD.S13767
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    • "Autism spectrum disorders (ASDs) represent a wide array of neurodevelopmental disorders characterized by restricted interest, defective social interactions, repetitive behaviors, and deficit in language and verbal communication that manifest within the first 3 years of life (1, 2). The complexity of ASD is evident both at the levels of symptoms variability and of causative factors. "
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    ABSTRACT: Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders characterized by deficits in social interaction and social communication, restricted interests, and repetitive behaviors. Many synaptic protein genes are linked to the pathogenesis of ASDs, making them prototypical synaptopathies. An array of mutations in the synapsin (Syn) genes in humans has been recently associated with ASD and epilepsy, diseases that display a frequent comorbidity. Syns are pre-synaptic proteins regulating synaptic vesicle traffic, neurotransmitter release, and short-term synaptic plasticity. In doing so, Syn isoforms control the tone of activity of neural circuits and the balance between excitation and inhibition. As ASD pathogenesis is believed to result from dysfunctions in the balance between excitatory and inhibitory transmissions in neocortical areas, Syns are novel ASD candidate genes. Accordingly, deletion of single Syn genes in mice, in addition to epilepsy, causes core symptoms of ASD by affecting social behavior, social communication, and repetitive behaviors. Thus, Syn knockout mice represent a good experimental model to define synaptic alterations involved in the pathogenesis of ASD and epilepsy.
    Frontiers in Pediatrics 09/2014; 2:94. DOI:10.3389/fped.2014.00094
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