Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons

Anna M Klawonn; Michael Fritz; Silvia Castany; Marco Pignatelli; Carla Canal; Fredrik Similä; Hugo A Tejeda; Julia Levinsson; Maarit Jaarola; Johan Jakobsson; Juan Hidalgo; Markus Heilig; Antonello Bonci; David Engblom

doi:10.1016/j.immuni.2020.12.016

Microglial activation elicits a negative affective state through prostaglandin-mediated modulation of striatal neurons

Immunity. 2021 Feb 9;54(2):225-234.e6. doi: 10.1016/j.immuni.2020.12.016. Epub 2021 Jan 20.

Authors

Affiliations

¹ Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
² Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden; Present address: Department of Forensic Psychiatry and Psychotherapy, University of Ulm, Ulm, Germany.
³ Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden.
⁴ Synaptic Plasticity Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, Baltimore, MD 21224, USA; Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, MO 63110, USA.
⁵ Institute of Neurosciences and Department of Cellular Biology, Physiology, and Immunology, Autonomous University of Barcelona, 08028 Barcelona, Spain.
⁶ Synaptic Plasticity Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
⁷ Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
⁸ Global Institutes on Addictions, Miami, FL 33132, USA.
⁹ Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden. Electronic address: david.engblom@liu.se.

PMID: 33476547
DOI: 10.1016/j.immuni.2020.12.016

Abstract

Microglia are activated in many neurological diseases and have been suggested to play an important role in the development of affective disorders including major depression. To investigate how microglial signaling regulates mood, we used bidirectional chemogenetic manipulations of microglial activity in mice. Activation of microglia in the dorsal striatum induced local cytokine expression and a negative affective state characterized by anhedonia and aversion, whereas inactivation of microglia blocked aversion induced by systemic inflammation. Interleukin-6 signaling and cyclooxygenase-1 mediated prostaglandin synthesis in the microglia were critical for the inflammation-induced aversion. Correspondingly, microglial activation led to a prostaglandin-dependent reduction of the excitability of striatal neurons. These findings demonstrate a mechanism by which microglial activation causes negative affect through prostaglandin-dependent modulation of striatal neurons and indicate that interference with this mechanism could milden the depressive symptoms in somatic and psychiatric diseases involving microglial activation.

Keywords: DREADDs; Microglia; anhedonia; aversion; depression; interleukin-6; neuroinflammation; prostaglandin; striatum.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anhedonia / physiology*
Animals
Animals, Genetically Modified
Behavior, Animal
Cells, Cultured
Corpus Striatum / immunology*
Depression / immunology*
Disease Models, Animal
Humans
Inflammation
Interleukin-6 / metabolism
Macrophage Activation
Mice
Microglia / immunology*
Neurogenic Inflammation
Neurons / physiology*
Prostaglandins / metabolism

Substances

Interleukin-6
Prostaglandins