Disruption of Cell-Type-Specific Molecular Programs of Medium Spiny Neurons in Autism

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Autism spectrum disorders (ASD) are complex neurodevelopmental conditions with strong genetic influences.
• Research has primarily focused on cortical mechanisms, yet subcortical circuits are increasingly implicated in ASD.

Purpose of the Study:

• To systematically map developmental and molecular changes in subcortical brain regions in an ASD mouse model.
• To identify cell-type-specific alterations in the human putamen associated with ASD.

Main Methods:

• Lineage profiling across five brain regions in an ASD mouse model.
• Single-nucleus multiomic profiling of human putamen from ASD and neurotypical donors.
• Gene regulatory network analysis.

Main Results:

• The striatum exhibited the most prominent developmental and molecular changes in the ASD mouse model.
• Human ASD putamen revealed cell-type-specific transcriptomic and regulatory alterations, converging on synaptic and energy metabolic dysfunctions in D1 striosome medium spiny neurons (MSNs).
• EGR3 and EGR1 were identified as key transcriptional regulators of ASD-associated programs in D1 MSNs.

Conclusions:

• The striatum is a central node for ASD convergence, indicating critical subcortical involvement.
• This study provides a multiomic resource for understanding the subcortical mechanisms underlying ASD.