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Fluoxetine Affects Differentiation of Midbrain Dopaminergic Neurons In Vitro
Department of Toxicology, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; Unit Toxicol Sci, Karolinska Institute, Södertälje, Sweden.
Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
Unit Work Environm Toxicol, Karolinska Institute, Stockholm, Sweden; Unit Toxicol Sci, Karolinska Institute, Södertälje, Sweden.
Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden.
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2018 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 94, no 4, p. 1220-1231Article in journal (Refereed) Published
Abstract [en]

Recent meta-analyses found an association between prenatal exposure to the antidepressant fluoxetine (FLX) and an increased risk of autism in children. This developmental disorder has been related to dysfunctions in the brains' rewards circuitry, which, in turn, has been linked to dysfunctions in dopaminergic (DA) signaling. The present study investigated if FLX affects processes involved in dopaminergic neuronal differentiation. Mouse neuronal precursors were differentiated into midbrain dopaminergic precursor cells (mDPCs) and concomitantly exposed to clinically relevant doses of FLX. Subsequently, dopaminergic precursors were evaluated for expression of differentiation and stemness markers using quantitative polymerase chain reaction. FLX treatment led to increases in early regional specification markers orthodenticle homeobox 2 (Otx2) and homeobox engrailed-1 and -2 (En1 and En2). On the other hand, two transcription factors essential for midbrain dopaminergic (mDA) neurogenesis, LIM homeobox transcription factor 1 alpha (Lmx1a) and paired-like homeodomain transcription factor 3 (Pitx3) were downregulated by FLX treatment. The stemness marker nestin (Nes) was increased, whereas the neuronal differentiation marker beta 3-tubulin (Tubb3) decreased. Additionally, we observed that FLX modulates the expression of several genes associated with autism spectrum disorder and downregulates the estrogen receptors (ERs) alpha and beta. Further investigations using ER beta knockout (BERKO) mDPCs showed that FLX had no or even opposite effects on several of the genes analyzed. These findings suggest that FLX affects differentiation of the dopaminergic system by increasing production of dopaminergic precursors, yet decreasing their maturation, partly via interference with the estrogen system.

Place, publisher, year, edition, pages
New York: American Society for Pharmacology and Experimental Therapeutics , 2018. Vol. 94, no 4, p. 1220-1231
National Category
Neurosciences Computer and Information Sciences
Identifiers
URN: urn:nbn:se:oru:diva-83056DOI: 10.1124/mol.118.112342ISI: 000445669700013PubMedID: 30115672Scopus ID: 2-s2.0-85054388432OAI: oai:DiVA.org:oru-83056DiVA, id: diva2:1439426
Funder
Swedish Research Council, 210-2012-1502Swedish Research Council Formas, 216-2013-1966
Note

Ytterligare forskningsfinansiär: Emil and Wera Cornell's research foundation

Available from: 2018-10-15 Created: 2020-06-12 Last updated: 2020-07-17Bibliographically approved

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