Identifying foetal forebrain interneurons as a target for monogenic autism risk factors and the polygenic 16p11.2 microdeletion.

Scientists studied how certain genetic changes linked to autism affect brain development. They looked at developing brain tissue and found that specific brain cells (interneurons) that help control brain activity are particularly vulnerable to autism-related genetic changes. In a rat model with similar genetic changes, these cells became overactive, which might explain some autism-related differences in brain function.

This 2023 study investigated how genetic autism risk factors, particularly the 16p11.2 microdeletion, affect inhibitory neuron development in the brain. Researchers analyzed human fetal brain tissue (8-26 weeks gestation) and examined a rat model of 16p11.2 deletion at 21 days postnatal. They identified specific interneurons in human fetal cortex (appearing at 23 weeks gestation) that express many autism risk genes, including those from the 16p11.2 region. In the rat model, while overall neuron numbers and positioning were normal, specific inhibitory neurons in the hippocampus showed hyperexcitability and enlarged axon initial segments, suggesting altered brain connectivity patterns.

Findings suggest 16p11.2 microdeletion affects interneuron function rather than development, potentially informing therapeutic targets. The identified vulnerable interneuron populations may represent biomarkers for early intervention timing during critical developmental windows.

Analysis limited to 8-26 week gestational period, single time point (P21) in rats, and single interneuron subtype. Human data from cortex only, not other brain regions. Cannot infer effects on cells not present during studied developmental stages.

Autism spectrum condition or 'autism' is associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. The balance between excitatory and inhibitory neurons in the cerebral cortex is hypothesised to be critical for the aetiology of autism making improved understanding of how risk factors impact on the development of these cells an important area of research. In the current study we aim to combine bioinformatics analysis of human foetal cerebral cortex gene expression data with anatomical and electrophysiological analysis of a 16p11.2rat model to investigate how genetic risk factors impact on inhibitory neuron development. We performed bioinformatics analysis of single cell transcriptomes from gestational week (GW) 8-26 human foetal prefrontal cortex and anatomical and electrophysiological analysis of 16p11.2rat cerebral cortex and hippocampus at post-natal day (P) 21.

We identified a subset of human interneurons (INs) first appearing at GW23 with enriched expression of a large fraction of risk factor transcripts including those expressed from the 16p11.2 locus. This suggests the hypothesis that these foetal INs are vulnerable to mutations causing autism. We investigated this in a rat model of the 16p11.2 microdeletion. We found no change in the numbers or position of either excitatory or inhibitory neurons in the somatosensory cortex or CA1 of 16p11.2rats but found that CA1 Sst INs were hyperexcitable with an enlarged axon initial segment, which was not the case for CA1 pyramidal cells.

The human foetal gene expression data was acquired from cerebral cortex between gestational week (GW) 8 to 26. We cannot draw inferences about potential vulnerabilities to genetic autism risk factors for cells not present in the developing cerebral cortex at these stages. The analysis 16p11.2rat phenotypes reported in the current study was restricted to 3-week old (P21) animals around the time of weaning and to a single interneuron cell-type while in human 16p11.2 microdeletion carriers symptoms likely involve multiple cell types and manifest in the first few years of life and on into adulthood. We have identified developing interneurons in human foetal cerebral cortex as potentially vulnerable to monogenic autism risk factors and the 16p11.2 microdeletion and report interneuron phenotypes in post-natal 16p11.2rats.