Translational profiling of mouse dopaminoceptive neurons reveals region-specific gene expression, exon usage, and striatal prostaglandin E2 modulatory effects

Enrica Montalban, Albert Giralt, Lieng Taing, Evelien H.S. Schut, Laura F. Supiot, Laia Castell, Yuki Nakamura, Benoit de Pins, Assunta Pelosi, Laurence Goutebroze, Pola Tuduri, Wei Wang, Katrina Daila Neiburga, Letizia Vestito, Julien Castel, Serge Luquet, Angus C. Nairn, Denis Hervé, Nathaniel Heintz, Claire MartinPaul Greengard, Emmanuel Valjent, Frank J. Meye, Nicolas Gambardella, Jean Pierre Roussarie, Jean Antoine Girault

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2068-2079
Number of pages12
JournalMolecular Psychiatry
Volume27
Issue number4
DOIs
Publication statusPublished - Apr 2022

Field of Science*

  • 3.1 Basic medicine
  • 3.2 Clinical medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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