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

•Microglia structure, function, and proteome profile is altered mainly in NLGN4-/- male mice.•P2YR12-dependent microglial signaling is altered only in NL4GN-/- male mice.•The NL4GN mutation alters gamma oscillations in a sex-specific manner.•Estrogen treatment restored P2YR12 signaling in NL4GN-/- m...

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Published in:Brain, behavior, and immunity behavior, and immunity, 2023-07, Vol.111, p.61-75
Main Authors: Guneykaya, Dilansu, Ugursu, Bilge, Logiacco, Francesca, Popp, Oliver, Feiks, Maria Almut, Meyer, Niklas, Wendt, Stefan, Semtner, Marcus, Cherif, Fatma, Gauthier, Christian, Madore, Charlotte, Yin, Zhuoran, Çınar, Özcan, Arslan, Taner, Gerevich, Zoltan, Mertins, Philipp, Butovsky, Oleg, Kettenmann, Helmut, Wolf, Susanne A.
Format: Article
Language:English
Subjects:
Animals
Autism spectrum disorder
Autism Spectrum Disorder - genetics
Female
Gamma oscillation
Life Sciences
Male
Medicin och hälsovetenskap
Mice
Mice, Knockout
Microglia
Neurons - physiology
Proteomics
Purinergic signaling
Sex difference
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Summary:•Microglia structure, function, and proteome profile is altered mainly in NLGN4-/- male mice.•P2YR12-dependent microglial signaling is altered only in NL4GN-/- male mice.•The NL4GN mutation alters gamma oscillations in a sex-specific manner.•Estrogen treatment restored P2YR12 signaling in NL4GN-/- male mice. 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.
ISSN:0889-1591
1090-2139
1090-2139
DOI:10.1016/j.bbi.2023.03.023