Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in children with idiopathic autism-Reference-Cited by-同舟云学术

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

Published:2024-05-01 Issue:13 Volume:34 Page:161-171
ISSN:1047-3211
Container-title:Cerebral Cortex
language:en
Short-container-title:

Author:

Fatemi S Hossein¹^ORCID,Eschenlauer Arthur²^ORCID,Aman Justin¹,Folsom Timothy D³⁴⁵⁶,Chekouo Thierry⁷

Affiliation:

1. University of Minnesota Medical School Department of Psychiatry and Behavioral Sciences, , 420 Delaware Street SE, Minneapolis, MN 55455, USA

2. Minnesota Supercomputing Institute , 599 Walter Library, 117 Pleasant Street, Minneapolis, MN 55455, USA

3. University of Minnesota Medical School Department of Pediatrics, , Minneapolis, MN 55455, USA

4. University of Minnesota Medical School Masonic Cancer Center, , Minneapolis, MN 55455, USA

5. University of Minnesota Medical School Center for Genome Engineering, , Minneapolis, MN 55455, USA

6. University of Minnesota Medical School Stem Cell Institute, , Minneapolis, MN 55455, USA

7. University of Minnesota School of Public Health , Minneapolis, MN 55455, USA

Abstract

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.

Funder

Autism Research Institute

Publisher

Oxford University Press (OUP)

Link

https://academic.oup.com/cercor/article-pdf/34/13/161/57370356/bhae044.pdf

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