Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG.

Scientists studied how certain antibodies from mothers during pregnancy might cause autism-like symptoms in their children. They found these antibodies affect immune cells in the brain, leading to social difficulties and brain changes in male offspring. The good news is that an existing blood pressure medication called captopril was able to reverse these problems when given to the affected mice, restoring normal brain function and social behavior.

This preclinical study investigated how maternal antibodies against brain protein Caspr2 affect offspring development and whether treatment can reverse autism-like symptoms. Researchers found that in utero exposure to anti-Caspr2 antibodies caused persistent microglial activation, reduced brain connectivity, and social behavior deficits in male mice. The blood-brain barrier permeable ACE inhibitor captopril successfully reversed these changes by restoring microglial function, improving brain structure, and normalizing social behavior. Single-cell analysis revealed captopril corrected disrupted cellular metabolism and protein synthesis pathways in microglia.

The study suggests that some cases of autism involving microglial dysfunction might be treatable with existing medications like captopril, though human trials are needed.

Results suggest that ACE inhibitors like captopril may benefit individuals with autism involving microglial dysfunction, particularly males with maternal anti-Caspr2 antibody exposure. However, human clinical trials are essential before considering therapeutic applications. The study supports investigating microglial markers as potential biomarkers for treatment selection.

This is a preclinical mouse study with unclear sample sizes. The findings may not translate directly to humans. The study focuses on a specific subset of autism cases involving anti-Caspr2 antibodies, limiting generalizability to broader autism populations.

Microglia play a crucial role in brain development, including synaptic pruning and neuronal circuit formation. Prenatal disruptions, such as exposure to maternal autoantibodies, can dysregulate microglial function and contribute to neurodevelopmental disorders like autism spectrum disorder (ASD). Maternal antibodies targeting the brain protein Caspr2, encoded by ASD risk gene Cntnap2, are found in a subset of mothers of children with ASD. In utero exposure to these antibodies in mice leads to an ASD-like phenotype in male but not in female mice, characterized by altered hippocampal microglial reactivity, reduced dendritic spine density, and impaired social behavior.

Here, we studied the role of microglia in mediating the effect of in utero exposure to maternal anti-Caspr2 antibodies and whether we can ameliorate this phenotype. In this study we demonstrate that microglial reactivity emerges early in postnatal development and persists into adulthood following exposure in utero to maternal anti-Caspr2 IgG. Captopril, a blood-brain barrier permeable angiotensin-converting enzyme (ACE) inhibitor, but not enalapril (a non-BBB permeable ACE inhibitor) ameliorates these deficits. Captopril treatment reversed microglial activation, restored spine density and dendritic arborization in CA1 hippocampal pyramidal neurons, and improved social interaction.

Single-cell RNA sequencing of hippocampal microglia identified a captopril-responsive subcluster exhibiting downregulated translation (eIF2 signaling) and metabolic pathways (mTOR and oxidative phosphorylation) in mice exposed in utero to anti-Caspr2 antibodies treated with saline compared to saline-treated controls. Captopril reversed these transcriptional alterations, restoring microglial homeostasis. Our findings suggest that exposure in utero to maternal anti-Caspr2 antibodies induces sustained neuronal alterations, microglial reactivity, and metabolic dysfunction, contributing to the social deficits in male offspring. BBB-permeable ACE inhibitors, such as captopril, warrant further investigation as a potential therapeutic strategy in a subset of ASD cases associated with microglial reactivity.