Synaptic Signaling and Aberrant RNA Splicing in Autism Spectrum Disorders

Ryan M Smith,Wolfgang Sadee

doi:10.3389/fnsyn.2011.00001

Ryan M Smith, Wolfgang Sadee

Open Access

https://doi.org/10.3389/fnsyn.2011.00001

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Abstract

Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of CAM RNAs, which ultimately determines neurotransmitter phenotype. The diverse assortment of RNAs produced by alternative splicing generates countless protein isoforms necessary for guiding specialized cell-to-cell connectivity. Failure to generate the appropriate synaptic adhesion proteins is associated with disrupted glutamatergic and gamma-aminobutyric acid signaling, resulting in loss of activity-dependent neuronal plasticity, and risk for developmental disorders, including autism. While the majority of genetic mutations currently linked to autism are rare variants that change the protein-coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in numerous other diseases, accounting for an estimated 40–60% of general disease risk. Here, we review the relationship between aberrant RNA splicing of synapse-related genes and autism spectrum disorders.

Highlights

Genome-wide association studies, analyses of copy number variants, DNA sequencing approaches, and familial linkage studies have revealed a number of autism risk genes encoding cellular adhesion molecules (CAMs) and synaptic scaffold proteins
Subsequent attempts to find single nucleotide polymorphisms (SNPs) conferring risk within CAM and scaffold genes have revealed few disease-causing coding variants shared among affected individuals (Vincent et al, 2004; Gauthier et al, 2005, 2009; Yan et al, 2005, 2008; Ylisaukko-oja et al, 2005; Blasi et al, 2006; Feng et al, 2006; Durand et al, 2007; Berkel et al, 2010)
Constitutive and alternative splicing is directed by a nuclear protein aggregate of more than 100 core proteins and secondary modulators, collectively known as the spliceosome, which interacts with heterogeneous nuclear RNA [hnRNA or pre-messenger RNA] in a process highly conserved in eukaryotes (Zhou et al, 2002)

Summary

Synaptic signaling and aberrant RNA splicing in autism spectrum disorders

Reviewed by: Peter Scheiffele, University of Basel, Switzerland Kelsey Martin, University of California Los Angeles, USA. Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. These trans-synaptic interactions are regulated by alternative splicing of CAM RNAs, which determines neurotransmitter phenotype. Failure to generate the appropriate synaptic adhesion proteins is associated with disrupted glutamatergic and gammaaminobutyric acid signaling, resulting in loss of activity-dependent neuronal plasticity, and risk for developmental disorders, including autism. While the majority of genetic mutations currently linked to autism are rare variants that change the protein-coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in numerous other diseases, accounting for an estimated 40–60% of general disease risk. We review the relationship between aberrant RNA splicing of synapse-related genes and autism spectrum disorders

Introduction

Smith and Sadee

Findings

Discussion