JMJD3 Deficiency in Midbrain Dopamine Neurons Disturbs Dopamine Synthesis and Aggravates Chronic Inflammatory Pain

Abstract

Regulation of dopamine (DA) biosynthesis is critical for the functionalities of midbrain DA neurons. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for dopamine (DA) biosynthesis in midbrain DA neurons. Here we report that DA contents are decreased in the midbrain and striatum of DA neuron-specific JMJD3 conditional knockdown mice. Consistent results are obtained from mice underwent pharmaceutical JMJD3 inhibition. Biochemical and histological experiments reveal that TH mRNA and protein levels are specifically decreased in DA neurons residing in ventral tegmental area but not substantia nigra pars compacta. On behavioral level, JMJD3 knockdown affects inflammation-induced chronic mechanical hyperalgesia but not locomotor coordination, corresponding to DA-associated behavior in ventral tegmental area and in substantia nigra pars compacta, respectively. Mechanistically, using a midbrain DA neuron culture, we demonstrate that JMJD3 transactivates TH gene expression through direct binding onto TH promoter and catalyzing H3K27 de-methylation. In summary, our findings reveal a novel role of JMJD3 in adult midbrain DA system and suggest its functional specificity with DA subtype heterogeneity.