Sex-specific microglia state in the Neuroligin-4 knock-out mouse model of autism spectrum disorder
Brain, Behavior, and Immunity. 2023-07-01; 111: 61-75
DOI: 10.1016/j.bbi.2023.03.023
Read on PubMed
Guneykaya D(1), Ugursu B(2), Logiacco F(3), Popp O(4), Feiks MA(5), Meyer N(6), Wendt S(3), Semtner M(2), Cherif F(3), Gauthier C(7), Madore C(8), Yin Z(7), Çınar Ö(9), Arslan T(10), Gerevich Z(5), Mertins P(4), Butovsky O(11), Kettenmann H(12), Wolf SA(13).
Author information:
(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: .
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.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.