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

• Published in: Cerebral cortex (New York, N.Y. 1991) N.Y. 1991), 2024-05, Vol.34 (13), p.161-171
• Main Authors: Fatemi, S Hossein, Eschenlauer, Arthur, Aman, Justin, Folsom, Timothy D, Chekouo, Thierry
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autistic Disorder - genetics; Autistic Disorder - metabolism; Child; Child, Preschool; Dorsolateral Prefrontal Cortex - metabolism; Female; Humans; Male; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Original; Post-Synaptic Density - metabolism; Prefrontal Cortex - metabolism; Proteomics; Synapses - metabolism; Synaptosomes - metabolism; Young Adult
• ISSN: 1047-3211; 1460-2199; 1460-2199
• DOI: 10.1093/cercor/bhae044

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