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.

Network Approach to Autistic Traits: Group and Subgroup Analyses of ADOS Item Scores

“…Applications to neuropsychiatry (as opposed to well characterized medical disorders and diseases) at the behavioral symptom level will initially be concerned with understanding behavioral level dynamics cross-sectionally and with network development. While network analyses have been widely applied in the field of autism research to genetic (Voineagu et al 2011;Veenstra-VanderWeele and Blakely 2012), neuroimaging (Anderson et al 2011) and metabolic data (Noto et al 2014), there has been very limited application at the behavioral or symptom level. In one report, Lyalina et al (2013) used a large medical data base in an attempt to discern what medical conditions and psychiatric conditions co-occurred with autism diagnoses.…”

Autistic-Like Syndrome in Mu Opioid Receptor Null Mice is Relieved by Facilitated mGluR4 Activity

“…Secondary-comorbid-symptoms vary substantially and include anxiety disorders, cognitive and motor deficits, aggressive behavior, and epileptic episodes (Johnson and Myers, 2007;Mazurek et al, 2013;Pouw et al, 2013;Robinson, 2012;Veenstra-VanderWeele and Blakely, 2012;White et al, 2012;Whyatt and Craig, 2013). Heterogeneity in ASDs points toward multiple primary causes, with genetic factors playing a critical role.…”

IRBIT regulates CaMKIIα activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation

“…In addition, the appropriate regulation of CaMKIIα is required for cognitive function and mood control (16)(17)(18). Thus, aberrant CaMKIIα activity is associated with several neuronal disorders such as schizophrenia, autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD), and drug addiction, in which hyperactivity and social abnormalities are frequently observed (19)(20)(21)(22)(23). However, the precise mechanism linking CaMKIIα dysregulation and mental disorders is poorly understood.…”