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Updated: Jun 27, 2025
High Resolution Quantitative Synaptic Proteome Profiling of Mouse Brain Regions After Auditory Discrimination Learning
Published on: December 15, 2016
Quantitative proteomics of dorsolateral prefrontal cortex reveals an early pattern of synaptic dysmaturation in
S Hossein Fatemi1, Arthur Eschenlauer2, Justin Aman1
1Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Insights
Autism spectrum disorder (ASD) involves synaptic deficits in the prefrontal cortex, particularly in children. Proteomic analysis revealed downregulated postsynaptic density proteins, suggesting a synaptopathy linked to ASD risk genes.
Area of Science:
- Neuroscience
- Proteomics
- Developmental Biology
Background:
- Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with increasing prevalence and poorly understood causes.
- Cognitive deficits and behavioral abnormalities are key features of ASD, particularly in childhood.
- The prefrontal cortex plays a crucial role in cognitive functions affected by ASD.
Purpose of the Study:
- To investigate the synaptic proteome of the prefrontal cortex in individuals with ASD to identify biological underpinnings of cognitive deficits.
- To compare proteomic signatures between children and adults with ASD and neurotypical controls.
Main Methods:
- Subcellular fractions of synaptosomes were isolated from prefrontal cortices of age-, brain area-, and postmortem-interval-matched children and adults with idiopathic ASD and controls.
- High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was employed for proteomic analysis.
- Bioinformatic analyses, including network analysis, were performed on the proteomic data.
Main Results:
- Proteomic analysis revealed significant downregulation of postsynaptic density (PSD)-related proteins in children with ASD, including AMPA/NMDA receptors, Shank, Homer, and neurexin/neuroligin families (FDR < 0.05).
- ASD risk genes involved in PSD structure and function maturation were enriched.
- These PSD-related alterations were less pronounced or absent in adult individuals with ASD.
- Network analyses indicated abnormalities in glutamate receptor signaling pathways.
Conclusions:
- The findings support the hypothesis that idiopathic ASD is a synaptopathy, specifically involving the PSD.
- Disruptions in the slow maturation of the PSD complex in the prefrontal cortex, influenced by ASD risk genes, may contribute to ASD development.
- The observed proteomic changes are more prominent in childhood ASD, suggesting developmental timing is critical.
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.
