Prenatal maternal immune activation triggers lasting cell-specific transcriptomic dysregulation in the amygdala of
Bradley P Ander1,2, Erin L Carlson2,3, Shawn Kamboj4,5
1Department of Neurology, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
Insights
Prenatal immune activation in mothers can alter fetal brain development, increasing neurodevelopmental disorder risk. This primate study reveals lasting gene expression changes in the amygdala, linking early inflammation to autism and psychosis pathways.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Prenatal exposure to maternal immune activation (MIA) is linked to neurodevelopmental disorders like autism (ASD) and schizophrenia.
- Cellular and molecular mechanisms connecting early inflammation to long-term brain dysfunction are not fully understood.
- Rodent models of MIA have limitations in translational relevance to human neurodevelopment.
Purpose of the Study:
- To investigate how transient maternal immune responses in early gestation affect gene expression in the nonhuman primate (NHP) amygdala.
- To identify specific cell types and molecular pathways affected by MIA in the developing primate brain.
- To establish a translational primate model for studying prenatal immune insults and neurodevelopmental disorders.
Main Methods:
- Utilized a nonhuman primate (NHP) model of maternal immune activation (MIA) by administering Poly(I:C) to pregnant macaques.
- Collected amygdala tissue from 4-year-old male offspring for single-nucleus RNA sequencing (snRNA-seq).
- Analyzed over 71,000 nuclei to identify differentially expressed genes (DEGs) in specific amygdala cell populations.
Main Results:
- Identified 2768 unique differentially expressed genes (DEGs) in the amygdala of offspring exposed to MIA.
- DEGs were concentrated in excitatory/inhibitory neurons of the lateral nucleus and microglia of the central nucleus.
- MIA-associated DEGs implicate synaptic structure, neurotransmission, and neuroimmune signaling, and significantly overlap with ASD and psychosis risk genes.
Conclusions:
- Transient prenatal maternal immune responses cause lasting, region- and cell-type-specific transcriptomic alterations in the primate amygdala.
- These findings provide a direct link between early immune activation and human neurodevelopmental disease pathways.
- The NHP MIA model offers a translational framework for understanding early immune insults and developing interventions for neurodevelopmental disorders.
Abstract:
Prenatal exposure to a heightened maternal immune response, such as that triggered by viral infection in the mother, can alter fetal brain development and increase risk of neurodevelopmental disorders in offspring, including autism (ASD) and schizophrenia. However, the cellular and molecular mechanisms linking early inflammatory signals to long-term changes in brain function remain unclear. While rodent models of maternal immune activation (MIA) display brain and behavioral disruptions, their translational relevance to humans is limited. To address this gap, we utilized a nonhuman primate (NHP) MIA model to examine how transient maternal immune responses in early gestation alter gene expression in the amygdala-a brain region essential for socioemotional behavior and implicated many neurodevelopmental disorders. Pregnant macaques were administered the viral mimic Poly(I:C) during the late first trimester, and amygdala samples were collected from 4-year-old male offspring for single-nucleus RNA sequencing (>71,000 nuclei). We identified 2768 unique differentially expressed genes (DEGs), concentrated in excitatory and inhibitory neurons of the lateral nucleus and microglia of the central nucleus. These DEGs converge on synaptic structure, neurotransmission, and neuroimmune signaling-core processes in circuit assembly and behavioral regulation. MIA-associated DEGs significantly overlap with high-confidence ASD- and psychosis-risk gene sets, directly linking prenatal immune events to human disease pathways. This study provides the first region- and cell-type-specific evidence in a primate model that transient prenatal maternal immune responses lead to lasting transcriptomic dysregulation. These findings reveal how early immune insults may alter neurodevelopment and offer a translational framework for identifying molecular targets for early intervention.
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