Characterizing autism spectrum disorders by key biochemical pathways

Abstract

The genetic and phenotypic heterogeneity of autism spectrum disorders (ASD) presents a substantial challenge for diagnosis, classification, research, and treatment. Investigations into the underlying molecular etiology of ASD have often yielded mixed and at times opposing findings. Defining the molecular and biochemical underpinnings of heterogeneity in ASD is crucial to our understanding of the pathophysiological development of the disorder, and has the potential to assist in diagnosis and the rational design of clinical trials. In this review, we propose that genetically diverse forms of ASD may be usefully parsed into entities resulting from converse patterns of growth regulation at the molecular level, which lead to the correlates of general synaptic and neural overgrowth or undergrowth. Abnormal brain growth during development is a characteristic feature that has been observed both in children with autism and in mouse models of autism. We review evidence from syndromic and non-syndromic ASD to suggest that entities currently classified as autism may fundamentally differ by underlying pro- or anti-growth abnormalities in key biochemical pathways, giving rise to either excessive or reduced synaptic connectivity in affected brain regions. We posit that this classification strategy has the potential not only to aid research efforts, but also to ultimately facilitate early diagnosis and direct appropriate therapeutic interventions.

Keywords: ERK signaling; MAP kinase signaling system; autism spectrum disorders (ASD); mTOR pathway; neurotrophic factors; protein synthesis.

Figure 1

Model depicting a proposed classification of different subtypes of ASD based on correlates of growth state. Neural overgrowth and undergrowth phenotypes have been associated with aberrant regulation of growth control pathways in autism spectrum disorders. Characteristic overgrowth and undergrowth phenotypes can be observed consistently from molecular to cellular and network levels. (A) Upregulation of pro-growth pathways can lead to: macrocephaly (Courchesne et al., 2003, 2007) aberrant overconnectivity of neuronal networks (Meikle et al., ; Keown et al., ; Supekar et al., 2013) increased survival and proliferation at the cellular level (Castrén et al., ; Callan et al., 2010) increased synaptic growth at the subcellular level (Irwin et al., ; Jaworski et al., ; Kwon et al., ; Tang et al., 2014), excessive protein synthesis (Osterweil et al., ; Santini et al., 2013) and/or a selective protein synthesis program enhancing production of growth-promoting proteins. (B) In contrast, hypoactive growth pathways lead to microcephaly, (Bronicki et al., ; Van Bon et al., 2015) underconnectivity of neuronal networks (Assaf et al., ; Anderson, 2014) decreased survival and proliferation at the cellular level (Yufune et al., 2015), decreased synaptic growth at the subcellular level (Cheng et al., 2014), decreased protein synthesis (Li et al., ; Tian et al., 2015) and/or a protein synthesis program that does not promote growth. These example phenotypes of undergrowth and overgrowth can be used as readouts for categorization of growth status in autism spectrum disorders.