Biology subjects

Mocci, E.

Publications and source records attributed to Mocci, E..

2 recordsLinked to original sources

bioRxiv2023

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

There is an increased incidence of autism among the children of women who take the anti-epileptic, mood stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration revealed that VPA significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of genes associated with neurodevelopmental disorders (NDDs) such as autism as well as neurogenesis, axon growth and synaptogenesis, GABAergic, glutaminergic and dopaminergic synaptic transmission, perineuronal nets, and circadian rhythms was dysregulated by VPA. Moreover, expression of 399 autism risk genes was significantly altered by VPA as was expression of 252 genes that have been reported to play fundamental roles in the development of the nervous system but are not otherwise linked to autism. The goal of this study was to identify mouse genes that are: (a) significantly up- or down-regulated by VPA in the fetal brain and (b) known to be associated with autism and/or to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity in the postnatal and adult brain. The set of genes meeting these criteria provides potential targets for future hypothesis-driven approaches to elucidating the proximal underlying causes of defective brain connectivity in NDDs such as autism.

neuroscience↗

bioRxiv2022

Early-childhood inflammation blunts the transcriptional maturation of cerebellar neurons

Inflammation early in life is a clinically established risk factor for autism spectrum disorders and schizophrenia, yet the impact of inflammation on human brain development is poorly understood. The cerebellum undergoes protracted postnatal maturation, making it especially susceptible to perturbations contributing to risk of neurodevelopmental disorders. Here, using single-cell genomics, we characterize the postnatal development of cerebellar neurons and glia in 1-5-year-old children, comparing those who died while experiencing inflammation vs. non-inflamed controls. Our analyses reveal that inflammation and postnatal maturation are associated with extensive, overlapping transcriptional changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons. Immunohistochemical analysis of a subset of these brains revealed no change to Purkinje neuron soma size but evidence for increased activation of microglia in those subjects experiencing inflammation. Maturation- and inflammation-associated genes were strongly enriched for those implicated in neurodevelopmental disorders. A gene regulatory network model integrating cell type-specific gene expression and chromatin accessibility identified seven temporally specific gene networks in Purkinje neurons and suggested that the effects of inflammation correspond to blunted cellular maturation. One Sentence SummaryPost-mortem cerebelli from children who perished under conditions that included inflammation exhibit transcriptomic changes consistent with blunted maturation of Purkinje neurons compared to those who succumbed to sudden accidental death.

genomics↗