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

Guneykaya D, Ugursu B, Logiacco F, Popp O, Feiks MA, Meyer N, Wendt S, Semtner M, Cherif F, Gauthier C, Madore C, Yin Z, Çınar Ö, Arslan T, Gerevich Z, Mertins P, Butovsky O, Kettenmann H, Wolf SA

Brain Behav. Immun. 111 (-) 61-75 [2023-07-00; online 2023-03-29]

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.

PubMed 37001827

DOI 10.1016/j.bbi.2023.03.023

Crossref 10.1016/j.bbi.2023.03.023

mid: NIHMS1892973
pmc: PMC10330133
pii: S0889-1591(23)00080-6