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.

Download full-text


Available from: Daniel Campbell, Jul 15, 2014
  • Source
    • "Autism spectrum disorders (ASD) consist of a group of heterogeneous neurodevelopmental disorders, with a high prevalence of ~1/100 children[1]. Core symptoms of ASD are deficits in social interaction and communication , together with restricted interests and repetitive be- haviors234. The etiology of ASD remains unclear, but a strong genetic component is evident. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A reduction of the number of parvalbumin (PV)-immunoreactive (PV + ) GABAergic interneurons or a decrease in PV immunoreactivity was reported in several mouse models of autism spectrum disorders (ASD). This includes Shank mutant mice, with SHANK being one of the most important gene families mutated in human ASD. Similar findings were obtained in heterozygous (PV+/-) mice for the Pvalb gene, which display a robust ASD-like phenotype. Here, we addressed the question whether the observed reduction in PV immunoreactivity was the result of a decrease in PV expression levels and/or loss of the PV-expressing GABA interneuron subpopulation hereafter called “Pvalb neurons”. The two alternatives have important implications as they likely result in opposing effects on the excitation/inhibition balance, with decreased PV expression resulting in enhanced inhibition, but loss of the Pvalb neuron subpopulation in reduced inhibition. Stereology was used to determine the number of Pvalb neurons in ASD-associated brain regions including the medial prefrontal cortex, somatosensory cortex and striatum of PV-/-, PV+/-, Shank1-/- and Shank3B-/- mice. As a second marker for the identification of Pvalb neurons, we used Vicia Villosa Agglutinin (VVA), a lectin recognizing the specific extracellular matrix enwrapping Pvalb neurons. PV protein and Pvalb mRNA levels were determined quantitatively by Western blot analyses and qRT-PCR, respectively. Our analyses of total cell numbers in different brain regions indicated that the observed “reduction of PV + neurons” was in all cases, i.e., in PV+/-, Shank1-/- and Shank3B-/- mice, due to a reduction in Pvalb mRNA and PV protein, without any indication of neuronal cell decrease/loss of Pvalb neurons evidenced by the unaltered numbers of VVA + neurons. Our findings suggest that the PV system might represent a convergent downstream endpoint for some forms of ASD, with the excitation/inhibition balance shifted towards enhanced inhibition due to the down-regulation of PV being a promising target for future pharmacological interventions. Testing whether approaches aimed at restoring normal PV protein expression levels and/or Pvalb neuron function might reverse ASD-relevant phenotypes in mice appears therefore warranted and may pave the way for novel therapeutic treatment strategies.
    Full-text · Article · Dec 2016 · Molecular Brain
  • Source
    • "It is the interaction between genes and the environment that determines individual ASD risk, clinical phenotype , and/or treatment outcome. Evidence supporting environmental contributions to ASD risk include observations of incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation, whereby a significant percentage of carriers do not express autistic phenotypes [14, 19, 22]. Two large, independent twin studies that examined the relative contributions of genetic heritability versus the shared environment similarly concluded that environmental factors were more predominant than genetic factors in determining autism risk [23, 24] . "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jan 2016
  • Source
    • "Based on genomic fidelity and copy number variations, PLCg1 has been assumed as a contributing genetic factor in neurodevelopmental disorders such as autism spectrum disorders (ASDs) (Persico et al., 2000; Bottini et al., 2001), hippocampal atrophy (Potkin et al., 2009) and attention deficit hyperactivity disorder (Lasky-Su et al., 2008). Many studies have suggested that the disruption of neurotrophin signaling on the PLCg1 pathway appears in various aspects of neurodevelopmental disorders (Levitt and Campbell, 2009). For example, dysregulation of BDNF signaling showed relevance of neurodevelopmental disorders such as ASDs (Al-Ayadhi, 2012; Binder, 2004; Binder and Scharfman, 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past decade, converging evidence suggests that PLCγ1 signaling has key roles in controlling neural development steps. PLCγ1 functions as a signal transducer that converts an extracellular stimulus into intracellular signals by generating second messengers such as DAG and IP3. DAG functions as an activator of either PKC or transient receptor potential cation channels (TRPCs), while IP3 induces the calcium release from intracellular calcium stores. These second messengers regulate the morphological change of neuron, such as neurite outgrowth, migration, axon pathfinding, and synapse formation. These morphological changes depend on finely tuned calcium signaling following receptor tyrosine kinase-mediated PLCγ1 signaling. Thus, deregulation of PLCγ1 signaling causes various abnormalities of neuronal development and it may be associated with diverse neurological disorders. Herein, we discuss the current understanding of the PLCγ1 signaling pathway in neural development and provide recent advances of how PLCγ1 signaling is involved in the formation of neuronal processes for functionally faithful brain development.
    Full-text · Article · Oct 2015 · Advances in Biological Regulation
Show more