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Neuron-specific transcriptomic signatures indicate neuroinflammation and altered neuronal activity in ASD temporal
Pan Zhang1,2,3, Alicja Omanska4,5, Bradley P Ander5,6
1Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Summary
Autism spectrum disorder (ASD) involves altered gene expression in brain neurons, particularly affecting inflammation and communication pathways. This study reveals cell-specific changes, offering potential therapeutic targets across the lifespan.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with significant heterogeneity.
- Transcriptomic studies of bulk brain tissue show common gene and pathway dysregulation in ASD.
- Bulk tissue analysis lacks cell-specific resolution, limiting understanding of cellular contributions to ASD pathophysiology.
Purpose of the Study:
- To investigate cell-specific transcriptomic alterations in the superior temporal gyrus (STG) of individuals with and without ASD.
- To identify age-dependent gene expression changes in ASD.
- To explore the interplay between neuroinflammation, neuronal pathways, and splicing in ASD.
Main Methods:
- Comprehensive transcriptomic analysis of bulk brain tissue and laser-capture microdissected (LCM) neurons from postmortem human brains.
- Analysis of 59 individuals (27 ASD, 32 controls) aged 2-73 years.
- Mechanistic modeling to link inflammation and gene expression.
Main Results:
- Bulk tissue analysis revealed altered synaptic signaling, heat shock protein pathways, and RNA splicing in ASD.
- LCM neuron analysis showed upregulated AP-1-mediated neuroinflammation and insulin/IGF-1 signaling, with downregulated mitochondrial function, ribosome, and spliceosome components.
- Key GABA synthesizing enzymes (GAD1, GAD2) were downregulated in ASD neurons, and alterations in small nucleolar RNAs (snoRNAs) suggested interplay with splicing disruption.
Conclusions:
- Findings support altered neuronal communication as a fundamental aspect of ASD.
- Neuroinflammation is elevated, at least partly within ASD neurons.
- Identified pathways and genes may represent therapeutic targets for ASD interventions across the lifespan.
