Work

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

Year: 2026

Type: article

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.

Source: Translational Psychiatry

DOI: 10.1038/s41398-026-04424-5

Authors: Yafeng Zhan, Cirong Liu, Zheng Wang