Maternal Herpesviridae infection during pregnancy alters midbrain dopaminergic signatures in adult offspring.

BACKGROUND:Motor symptoms of Parkinson's disease (PD) are apparent after a high proportion of dopamine neurons in the substantia nigra have degenerated. The vast majority of PD cases are sporadic, and the underlying pathobiological causes are poorly understood. Adults exhibit great variability in the numbers of nigral dopamine neurons, suggesting that factors during embryonic or early life regulate the development and physiology of dopaminergic neurons. Furthermore, exposure to infections and inflammation in utero has been shown to affect fetal brain development in models of schizophrenia and autism. Here, we utilize a mouse maternal infection model to examine how maternal herpesvirus infection impacts dopaminergic neuron-related gene and protein expression in the adult offspring. METHODS:Pregnant mice were injected with murine cytomegalovirus (MCMV), murine gamma herpes virus-68 (MHV68) or phosphate buffered saline (PBS) at embryonic day 8.5. Offspring were sacrificed at eight weeks of age and midbrains were processed for whole genome RNA sequencing, DNA methylation analysis, targeted protein expression and high-performance liquid chromatography for quantification of dopamine and its metabolites. RESULTS:The midbrain of adult offspring from MHV68 infected dams had significantly decreased expression of genes linked to dopamine neurons (Th, Lmx1b, and Foxa1) and increased Lrrk2, a gene involved in familial PD and PD risk that associates with neuroinflammation. Deconvolution analysis revealed that the proportion of dopamine neuron genes in the midbrain was reduced. There was an overall increase in DNA methylation in the midbrain of animals from MHV68-infected dams and pathway analyses indicated mitochondrial dysfunction, with reductions in genes associated with ATP synthesis, mitochondrial respiratory chain, and mitochondrial translation in the offspring of dams infected with MHV68. TIGAR (a negative regulator of mitophagy) and SDHA (mitochondrial complex II subunit) protein levels were increased, and the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum were increased in these offspring compared to offspring from uninfected control dams. No such changes were observed in the offspring of dams infected with MCMV. CONCLUSION:Our data suggest that maternal infection with Herpesviridae, specifically MHV68, can trigger changes in the development of the midbrain that impact dopamine neuron physiology in adulthood. Our work is of importance for the understanding of neuronal susceptibility underlying neurodegenerative disease, with particular relevance for PD.