Spatial and single-cell transcriptomics reveals senescence-associated changes in MIA-induced ASD male mouse brain.

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Autism spectrum disorder (ASD) is a complex neurodevelopmental condition.
• Maternal immune activation (MIA) is a known risk factor implicated in ASD neuropathology.
• The specific molecular mechanisms underlying ASD in MIA offspring remain largely unknown.

Purpose of the Study:

• To explore the neurobiological features and regulatory mechanisms of ASD in MIA offspring.
• To identify key genes and pathways involved in ASD development following MIA.
• To investigate potential therapeutic interventions targeting identified pathways.

Main Methods:

• Spatial transcriptome and single-nucleus RNA sequencing (snRNA-seq) analysis of MIA offspring brains.
• Identification of MIA-induced genes and pathways across multiple brain regions.
• Pharmacological inhibition of key identified genes (IGFBP7 and CDKN1A) in MIA offspring models.

Main Results:

• Discovery of a senescence-associated APP-CD74 pathway, IGFBP7, and CDKN1A as critical pathogenic factors in MIA-induced ASD.
• Identification of a broad senescence-associated secretory phenotype (SASP) signature in MIA-induced ASD brains, with cell-type specific regulation.
• Validation that inhibiting IGFBP7 and CDKN1A effectively ameliorates ASD-like behaviors in MIA offspring.

Conclusions:

• A senescence-associated regulatory mechanism contributes to ASD development following MIA.
• IGFBP7 and CDKN1A represent promising therapeutic targets for ASD treatment.
• This research provides novel insights into ASD pathogenesis and potential intervention strategies.