Neuron-specific transcriptomic signatures indicate neuroinflammation and altered neuronal activity in ASD temporal cortex

Abstract

Autism spectrum disorder (ASD) is a highly heterogeneous disorder, yet transcriptomic profiling of bulk brain tissue has identified substantial convergence among dysregulated genes and pathways in ASD. However, this approach lacks cell-specific resolution. We performed comprehensive transcriptomic analyses on bulk tissue and laser-capture microdissected (LCM) neurons from 59 postmortem human brains (27 ASD and 32 controls) in the superior temporal gyrus (STG) of individuals ranging from 2 to 73 years of age. In bulk tissue, synaptic signaling, heat shock protein-related pathways, and RNA splicing were significantly altered in ASD. There was age-dependent dysregulation of genes involved in gamma aminobutyric acid (GABA) ( GAD1 and GAD2 ) and glutamate ( SLC38A1 ) signaling pathways. In LCM neurons, AP-1-mediated neuroinflammation and insulin/IGF-1 signaling pathways were upregulated in ASD, while mitochondrial function, ribosome, and spliceosome components were downregulated. GABA synthesizing enzymes GAD1 and GAD2 were both downregulated in ASD neurons. Mechanistic modeling suggested a direct link between inflammation and ASD in neurons, and prioritized inflammation-associated genes for future study. Alterations in small nucleolar RNAs (snoRNAs) associated with splicing events suggested interplay between snoRNA dysregulation and splicing disruption in neurons of individuals with ASD. Our findings supported the fundamental hypothesis of altered neuronal communication in ASD, demonstrated that inflammation was elevated at least in part in ASD neurons, and may reveal windows of opportunity for biotherapeutics to target the trajectory of gene expression and clinical manifestation of ASD throughout the human lifespan.

Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

“…The change of mitochondrial function, energy metabolism, EIF2 signaling, immune functions, ubiquitination, and DNA repair were found in global proteomics of peripheral blood‐derived lymphoblasts with homozygous HERC2 variants 117 . A transcriptome suggested that mitochondrial function, ribosome, and spliceosome components were down‐regulated in postmortem brain of ASD 118 …”

“…125 A mechanistic modeling based on transcriptome suggested a direct link between inflammation and ASD in neurons. 118 Notedly, the MIA is a one of the common environmental risk factors of ASD pathology during pregnancy. [126][127][128] The adaptive immune pathway was enriched in maternal blood from mothers of children later diagnosed with ASD by transcriptome.…”

“…117 A transcriptome suggested that mitochondrial function, ribosome, and spliceosome components were down-regulated in postmortem brain of ASD. 118 A metabolic profiling of lymphoblastoid cells revealed a decreased tryptophan metabolism in ASD and showed a reduced generation of nicotinamide adenine dinucleotide (NADH), a critical energy carrier in mitochondria. 119 The metabolic clusters containing lactate or pyruvate, succinate, α-ketoglutarate, glycine, ornithine, and 4hydroxyproline highlighted potential dysregulation in amino acid and energy metabolism in ASD plasma.…”

“…A mechanistic modeling based on transcriptome suggested a direct link between inflammation and ASD in neurons 118 . Notedly, the MIA is a one of the common environmental risk factors of ASD pathology during pregnancy 126–128 .…”

Succinic semialdehyde dehydrogenase deficiency: A model of neurocircuit imbalances in autism and potential insight into new biomarkers

“…The cause of this has not been identified despite detailed clinical investigations. Parallel to the age‐related increase in the E:I cortical balance in individuals with SSADH deficiency, a recent study examining post‐mortem brains demonstrates that individuals with ASD lose GABAergic (inhibitory) cortical tone as they age through adolescence into adulthood 5 . Thus, the age‐related effect seen in SSADH deficiency may be a helpful model for the age‐related changes in other neurodevelopmental disorders across the lifespan.…”