Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism

Abstract

Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual.

Keywords: Brodmann area 9; autism; childhood; proteomics; synaptopathy.

Fig. 1

Expression of selected synaptic proteins and their associated proteins. Panels (a) and (b), are plots for children and adults, respectively, of −log₁₀ (adjusted P-value) vs. log₂ (fold-change) for all proteins, computed for adjusted P-value of linear models of protein concentration based on peptide quantitation. Synaptic and associated proteins are labeled when above the threshold of significance. Panels (c) and (d) represent heatmaps of quantitations for synaptic and associated proteins. Quantities are centered and standard-scaled for each protein. Proteins are hierarchically clustered using Pearson correlation as the distance metric (longer lines perpendicular to the axis indicate lower correlation) and the “ward.D2” agglomerative clustering method. Undetected or unquantitated proteins are marked “NA.”