let-7 microRNAs regulate microglial function and suppress glioma growth through Toll-like receptor 7

Microglia express Toll-like receptors (TLRs) that sense pathogen- and host-derived factors, including single-stranded RNA. In the brain, let-7 microRNA (miRNA) family members are abundantly expressed, and some have recently been shown to serve as TLR7 ligands. We investigated whether let-7 miRNA family members differentially control microglia biology in health and disease. We found that a subset of let-7 miRNA family members function as signaling molecules to induce microglial release of inflammatory cytokines, modulate antigen presentation, and attenuate cell migration in a TLR7-dependent manner. The capability of the let-7 miRNAs to control microglial function is sequence specific, mapping to a let-7 UUGU motif. In human and murine glioblastoma/glioma, let-7 miRNAs are differentially expressed and reduce murine GL261 glioma growth in the same sequence-specific fashion through microglial TLR7. Taken together, these data establish let-7 miRNAs as key TLR7 signaling activators that serve to regulate the diverse functions of microglia in health and glioma

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

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

Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment

Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer's disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders

Changes in phagocytosis and potassium channel activity in microglia of 5xFAD mice indicate alterations in purinergic signaling in a mouse model of Alzheimer's disease

As the immunocompetent cells of the central nervous system, microglia accumulate at amyloid beta plaques in Alzheimer's disease (AD) and acquire a morphological phenotype of activated microglia. Recent functional studies, however, indicate that in mouse models of amyloidosis and AD, these cells are rather dysfunctional indicated by a reduced phagocytic activity. Here, we report that this reduction in phagocytic activity is associated with perturbed purinergic receptor signaling, since phagocytosis could be stimulated by P2Y6 receptor activation in control, but not in 5xFAD transgenic animals, an animal model of amyloid deposition. Impaired phagocytosis is not innate, and develops only at later stages of amyloidosis. Furthermore, we show that membrane currents induced by uridine diphosphate, a ligand activating P2Y6 receptors, are altered in response rate and amplitude in microglia in close vicinity to plaques, but not in plaque-free areas of 5xFAD animals. These changes were accompanied by changes in membrane properties and potassium channel activity of plaque-associated microglia in early and late stages of amyloidosis. As a conclusion, the physiological properties of plaque-associated microglia are altered with a strong impact on purinergic signaling

Transcriptional and Translational Differences of Microglia from Male and Female Brains

Summary: Sex differences in brain structure and function are of substantial scientific interest because of sex-related susceptibility to psychiatric and neurological disorders. Neuroinflammation is a common denominator of many of these diseases, and thus microglia, as the brain’s immunocompetent cells, have come into focus in sex-specific studies. Here, we show differences in the structure, function, and transcriptomic and proteomic profiles in microglia freshly isolated from male and female mouse brains. We show that male microglia are more frequent in specific brain areas, have a higher antigen-presenting capacity, and appear to have a higher potential to respond to stimuli such as ATP, reflected in higher baseline outward and inward currents and higher protein expression of purinergic receptors. Altogether, we provide a comprehensive resource to generate and validate hypotheses regarding brain sex differences. : Guneykaya et al. provide transcriptomic, proteomic, and functional data from male and female microglia, providing a resource for further investigation of sex-based differences in microglia. Keywords: microglia, sex differences, transcriptomics, proteomic