Spatial transcriptional signatures linked to brain activity patterns in MECP2 transgenic monkeys and human autism spectrum disorder

Abstract

Imaging transcriptomics studies in autism spectrum disorder (ASD) have identified relevant biological pathways, yet the specific laminar molecular signatures associated with functional abnormalities remain largely unexplored. We integrated resting-state fMRI (rs-fMRI) data from methyl-CpG binding protein 2 (MECP2) transgenic monkeys—a model exhibiting autism-like behavior—with spatially resolved transcriptomic data to investigate layer-specific transcriptional signatures associated with altered brain activity. To evaluate their clinical relevance, we further projected these signatures onto human brain-wide gene expression data and examined their correlations with imaging alterations in ASD patients. Comparing to wild-type monkeys, MECP2 monkeys exhibited reduced brain activity in the prefrontal cortex and increased activity in the somatosensory cortices. These alterations were linked to expression profiles of two gene sets: one preferentially expressed in layers 2 and 6, primarily enriched in synaptic signaling; the other predominantly expressed in layer 3, primarily enriched in mitochondrial function. Additionally, two parvalbumin (PV) neuron subtypes showed opposing associations with alteration pattern: one concentrated in layer 5 of the prefrontal cortex; the other abundant in layers 3 and 4 of the somatosensory cortex. Projecting these transcriptional signatures onto human gene expression data revealed significant correlations with functional alterations in a subgroup of ASD patients. Our findings reveal layer-specific and cell-type-specific molecular signatures of MECP2-related brain dysfunction, offering insights into the biological basis of ASD and enhancing translational relevance across species.