Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration

Abstract

In the last two decades, microglia have emerged as key contributors to disease progression in many neurological disorders, not only by exerting their classical immunological functions but also as extremely dynamic cells with the ability to modulate synaptic and neural activity. This dynamic behavior, together with their heterogeneous roles and response to diverse perturbations in the brain parenchyma has raised the idea that microglia activation is more diverse than anticipated and that understanding the molecular mechanisms underlying microglial states is essential to unravel their role in health and disease from development to aging. The Ikzf1 (a.k.a. Ikaros) gene plays crucial roles in modulating the function and maturation of circulating monocytes and lymphocytes, but whether it regulates microglial functions and states is unknown. Using genetic tools, here we describe that Ikzf1 is specifically expressed in the adult microglia in brain regions such as cortex and hippocampus. By characterizing the Ikzf1 deficient mice, we observed that these mice displayed spatial learning deficits, impaired hippocampal CA3-CA1 long-term potentiation, and decreased spine density in pyramidal neurons of the CA1, which correlates with an increased expression of synaptic markers within microglia. Additionally, these Ikzf1 deficient microglia exhibited a severe abnormal morphology in the hippocampus, which is accompanied by astrogliosis, an aberrant composition of the inflammasome, and an altered expression of disease-associated microglia molecules. Interestingly, the lack of Ikzf1 induced changes on histone 3 acetylation and methylation levels in the hippocampus. Since the lack of Ikzf1 in mice appears to induce the internalization of synaptic markers within microglia, and severe gliosis we then analyzed hippocampal Ikzf1 levels in several models of neurological disorders. Ikzf1 levels were increased in the hippocampus of these neurological models, as well as in postmortem hippocampal samples from Alzheimer's disease patients. Finally, over-expressing Ikzf1 in cultured microglia made these cells hyporeactive upon treatment with lipopolysaccharide, and less phagocytic compared to control microglia. Altogether, these results suggest that altered Ikzf1 levels in the adult hippocampus are sufficient to induce synaptic plasticity and memory deficits via altering microglial state and function.

Keywords: Astrogliosis; Learning; Long-term potentiation; Memory; Synaptic engulfment; Synaptic plasticity.