Abstract: Aberrant neurodevelopment is a core deficit of autism spectrum disorder (ASD). Previously, we showed that adult mice prenatally exposed to non-apoptotic MeHg exhibited key ASD characteristics, including impaired communication, reduced sociability, and increased restrictive, repetitive behaviours, whereas, in the embryonic cortex, prenatal MeHg exposure caused premature neuronal differentiation. However, it remains unknown regarding underlying cellular mechanisms that contribute to prenatal MeHg-induced ASD. To determine underlying cellular mechanisms unbiasedly, we performed bulk RNA-seq analysis using cortical tissues from adult mice prenatally treated with 0.2ppm MeHg and revealed aberrantly increased cholinergic synaptic function. We further confirmed the finding by showing increased expression of choline acetyltransferase (Chat) in postnatal day 7 cortical tissues followed by increased expression of acetylcholine transporter (Slc5a7) in adult cortical tissues of mice receiving prenatal treatment of 0.2ppm MeHg. Intriguingly, we also observed an increased number of acetylcholine neurons (Chat+ cells) in the prefrontal cortex (PFC) of adult mice prenatally treated with 0.2 ppm MeHg. To ask about the embryonic origin of the increased Chat+ neurons in the prefrontal cortex, we performed embryonic day 12 (E12) dorsal and ventral neural precursor cultures and showed that non-apoptotic 25nM MeHg treatment in culture can increase the genesis of Chat+ neurons from both dorsal cortical precursors and ventral neural precursors. Overall, these results suggest that prenatal MeHg exposure increases cholinergic neuron production from embryonic neural precursors, consequently leading to dysregulated cholinergic neuron communication in adulthood, potentially contributing to ASD phenotypes.
Funding Source: The project is funded by the Natural Sciences and Engineering Council of Canada, the Canadian Institute of Health Research and the Canada Research Chair Program
