Reciprocal signaling between translational control pathways and synaptic proteins in autism spectrum disorders

Abstract

Autism spectrum disorder (ASD) is a heterogeneous group of heritable neurodevelopmental disorders whose symptoms, which include deficits in social interaction skills, impaired communication ability, and ritualistic-like repetitive behaviors, appear in early childhood and continue throughout life. Genetic studies have revealed at least two clusters of genes frequently associated with ASD and intellectual disability: genes encoding for proteins involved in translational control and proteins involved in synaptic function. We hypothesize that mutations occurring in these two clusters of genes interfere with interconnected downstream signaling pathways to cause ASD symptomatology. In this review, we focus on the monogenic forms of ASD caused by mutations in genes encoding for proteins that regulate translation and synaptic proteins. Specifically, we describe the function of these proteins, the intracellular signaling regulated by them, and the current mouse models utilized to characterize synaptic and behavioral features of these mutations. Finally, we summarize recent studies that have established a connection between these two signaling pathways in models of ASD and propose that dysregulation of one pathway has a detrimental impact of the other.

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

“…As categorized by putative function (activity-dependent transcription, glutamate regulation of local protein synthesis and synaptic plasticity, and alterations of E:I coordination and synaptic structure), all of these groups display a prominent autoregulatory aspect. We build upon excellent reviews on ASD that highlight the role of homeostasis (Ramocki and Zoghbi, 2008; Toro et al, 2010; Wondolowski and Dickman, 2013), the bidirectional communication between postsynaptic receptors and dendritic protein synthesis (Santini and Klann, 2014), and the influence of homeostasis on aberrant E:I coordination (Nelson and Valakh, 2015). We also take note of valuable categorizations of ASD-associated genes based on anatomical location or protein-protein interactions.…”

LTD-like molecular pathways in developmental synaptic pruning

“…In these mice, extracellular signal-related kinases 1 and 2 (ERK1/2) signaling is enhanced, which may increase eIF4E cap-dependent translation (for review, see ref. 125). Local cap-dependent mRNA translation is also controlled by mammalian target of rapamycin (mTOR), which in turn is negatively regulated by the tuberous sclerosis complex proteins TSC1 and TSC2 (TSC shows ASD comorbidity; for review, see ref.…”

Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice

“…Moreover, inhibition of components of the mTORC1 and ERK signaling pathways that couple mGluRs to protein synthesis normalizes aberrant phenotypes in FXS model mice (38, 39, 41–46). Finally, either genetic deletion of 4E-BP2 (47) or overexpression of eIF4E (48) generates ASD-like behaviors and altered synaptic function in mice similar to those displayed by FXS model mice, suggesting that dysregulation of signaling pathways that regulate protein synthesis is a common pathogenic pathway involved in both FXS and ASD (49, 50). …”