Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder

Dilansu Guneykaya; Bilge Ugursu; Francesca Logiacco; Oliver Popp; Maria Almut Feiks; Niklas Meyer; Stefan Wendt; Marcus Semtner; Fatma Cherif; Christian Gauthier; Charlotte Madore; Zhuoran Yin; Özcan Çınar; Taner Arslan; Zoltan Gerevich; Philipp Mertins; Oleg Butovsky; Helmut Kettenmann; Susanne A Wolf

doi:10.1016/j.bbi.2023.03.023

Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder

Brain Behav Immun. 2023 Jul:111:61-75. doi: 10.1016/j.bbi.2023.03.023. Epub 2023 Mar 29.

Authors

Dilansu Guneykaya¹, Bilge Ugursu², Francesca Logiacco³, Oliver Popp⁴, Maria Almut Feiks⁵, Niklas Meyer⁶, Stefan Wendt³, Marcus Semtner², Fatma Cherif³, Christian Gauthier⁷, Charlotte Madore⁸, Zhuoran Yin⁷, Özcan Çınar⁹, Taner Arslan¹⁰, Zoltan Gerevich⁵, Philipp Mertins⁴, Oleg Butovsky¹¹, Helmut Kettenmann¹², Susanne A Wolf¹³

Affiliations

¹ Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Neurobiology, Harvard Medical School, Boston, USA.
² Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Germany; Psychoneuroimmunology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
³ Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁴ Proteomics Platform, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute of Health, Berlin, Germany.
⁵ Institute of Neurophysiology, Charité - Universitätsmedizin, Berlin, Germany.
⁶ Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Microbiology, Oslo University Hospital, Oslo, Norway.
⁷ Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Univ. Bordeaux, INRA, Bordeaux INP, NutriNeuro, Bordeaux, France.
⁹ Molecular Immunotherapy, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin Institute of Health, Berlin, Germany.
¹⁰ Department of Oncology and Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.
¹¹ Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Germany.
¹² Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
¹³ Cellular Neuroscience, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Ophthalmology, Charité - Universitätsmedizin Berlin, Germany; Psychoneuroimmunology, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. Electronic address: susanne.wolf@charite.de.

Abstract

Neuroligin-4 (NLGN4) loss-of-function mutations are associated with monogenic heritable autism spectrum disorder (ASD) and cause alterations in both synaptic and behavioral phenotypes. Microglia, the resident CNS macrophages, are implicated in ASD development and progression. Here we studied the impact of NLGN4 loss in a mouse model, focusing on microglia phenotype and function in both male and female mice. NLGN4 depletion caused lower microglia density, less ramified morphology, reduced response to injury and purinergic signaling specifically in the hippocampal CA3 region predominantly in male mice. Proteomic analysis revealed disrupted energy metabolism in male microglia and provided further evidence for sexual dimorphism in the ASD associated microglial phenotype. In addition, we observed impaired gamma oscillations in a sex-dependent manner. Lastly, estradiol application in male NLGN4^-/- mice restored the altered microglial phenotype and function. Together, these results indicate that loss of NLGN4 affects not only neuronal network activity, but also changes the microglia state in a sex-dependent manner that could be targeted by estradiol treatment.

Keywords: Autism spectrum disorder; Gamma oscillation; Microglia; Purinergic signaling; Sex difference.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autism Spectrum Disorder* / genetics
Female
Male
Mice
Mice, Knockout
Microglia
Neurons / physiology
Proteomics

Abstract

Publication types

MeSH terms

Grants and funding