Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments

Abstract

Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder affecting approximately 1% of children. ASD is defined by core symptoms in two domains: negative symptoms of impairment in social and communication function, and positive symptoms of restricted and repetitive behaviors. Available treatments are inadequate for treating both core symptoms and associated conditions. Twin studies indicate that ASD susceptibility has a large heritable component. Genetic studies have identified promising leads, with converging insights emerging from single-gene disorders that bear ASD features, with particular interest in mammalian target of rapamycin (mTOR)-linked synaptic plasticity mechanisms. Mouse models of these disorders are revealing not only opportunities to model behavioral perturbations across species, but also evidence of postnatal rescue of brain and behavioral phenotypes. An intense search for ASD biomarkers has consistently pointed to elevated platelet serotonin (5-HT) levels and a surge in brain growth in the first 2 years of life. Following a review of the diversity of ASD phenotypes and its genetic origins and biomarkers, we discuss opportunities for translation of these findings into novel ASD treatments, focusing on mTor- and 5-HT-signaling pathways, and their possible intersection. Paralleling the progress made in understanding the root causes of rare genetic syndromes that affect cognitive development, we anticipate progress in models systems using bona fide ASD-associated molecular changes that have the potential to accelerate the development of ASD diagnostics and therapeutics.

Figure 1

ASD symptoms, comorbidities, and biomarkers. The core symptoms of ASD are represented in the center and represent the common features required to receive a diagnosis. All three social communication/social interaction symptoms are required to receive a diagnosis in the DSM-V draft criteria. This domain represents the ‘negative symptoms' of ASD, that is, absence of appropriate social communication. Two of the four restricted/repetitive behavior symptoms are required to receive a diagnosis in the DSM-V draft criteria. This domain represents the ‘positive symptoms' of ASD, that is, the presence of unusual restricted, repetitive, or sensory behaviors. Around the periphery of the figure are symptoms or biomarkers that are not required for an ASD diagnosis but are more common in ASD than in the general populations. Quite a number of comorbid disorders or symptoms are seen in a substantial minority or even a majority of individuals with ASD, spanning cognitive, behavioral/psychiatric, and medical domains. As might be expected from the range of comorbid symptoms, biomarkers and genetic findings also reveal significant heterogeneity across individuals with ASD.

Figure 2

Network of gene products connecting glutamate signaling to translation and synaptic plasticity. The network shown represents physical and signaling interactions between the gene products noted. mGluR5 is centrally located in this illustration to note its capacity for the regulation of both glutamate signaling through ionotropic glutamate receptors and mRNA translation through mTOR-linked signaling pathways. Convergence of FMR1 and TSC1/TSC2 gene products altered that signal through mTOR-linked translation control pathways, independent of mGluRs, are also shown.

Figure 3

Network of gene products regulating the expression, trafficking, and activity of the antidepressant-sensitive 5-HT transporters (SERT, SLC6A4). SERT controls the extracellular availability of 5-HT in the brain and periphery, and also recycles serotonin for further rounds of release. SERT-mediated clearance of 5-HT limits the amplitude and duration of signaling of more than a dozen 5-HT receptors. We hypothesize that just as risk for ASD can derive from genetic variation in SERT that impacts 5-HT signaling during brain development, risk for ASD can also be generated through environmental or genetic perturbations of SERT-regulatory control mechanisms.