Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson’s disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso/ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 (PGE2) was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a PGE2 receptor agonist, decreased the excitability of D2 striatal projection neurons in slices, and diminished their activity in vivo during novel environment exploration. We found that misoprostol also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target.
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DNA methylation and hydroxymethylation characterize the identity of D1 and D2 striatal projection neurons
Communications Biology Open Access 01 December 2022
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Sequencing data have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE137153.
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The paper is dedicated to the memory of PG who passed away on April 13th, 2019, before the paper was completed. Authors thank the Babraham Institute’s Bioinformatics team for help with read mapping and counting, Vincent Knight-Shrijver for his volcano-plot R script, and Lucile Marion-Poll for helpful suggestions.
This work was supported by Inserm and Sorbonne Université, and grants from European Research Council (ERC, AdG-250349) and Biology for Psychiatry Laboratory of excellence (Labex Bio-Psy, Investissements d’Avenir, ANR-11-IDEX-0004-02) to JAG, Fondation pour la Recherche Médicale (FRM # DPA20140629798) and ANR (Epitraces, ANR-16-CE16-0018) to JAG and EV, ANR-17-CE37-0007 (Metacognition) to CM, the United States Army Medical Research and Material Command (USAMRMC) Award No. W81XWH-14-1-0046 to JPR, the Fisher Center for Alzheimer’s Disease Research to JPR and PG, NIH grants DA018343 and DA040454 to ACN. EM was supported by a Marie Curie International Training Network (ITN) N-PLAST. AG is a Ramón y Cajal fellow (RYC-2016-19466) and is supported by a grant from the Spain Ministerio de Ciencia, Innovación y Universidades (Project no. RTI2018-094678-A-I00). LC was supported by a Labex EpiGenMed PhD fellowship (Investissements d’avenir, ANR-10-LABX-12-01). YN was recipient of Uehara Memorial Foundation and Fyssen Foundation fellowships. BdP was supported by FRM (FDT201805005390). NG was supported by BBSRC (BB/P013406/1, BB/P013414/1, BB/P013384/1). KDN received an Amgen Scholarship. LV received support from the Erasmus + program. Work in FJM lab was supported by the ERC under the European Union’s Horizon 2020 research and innovation program (grant agreement 804089; ReCoDE) and the NWO Gravitation project BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (024.004.012).
The authors declare no competing interests.
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Montalban, E., Giralt, A., Taing, L. et al. Translational profiling of mouse dopaminoceptive neurons reveals region-specific gene expression, exon usage, and striatal prostaglandin E2 modulatory effects. Mol Psychiatry 27, 2068–2079 (2022). https://doi.org/10.1038/s41380-022-01439-4
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