Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice

Abstract

Disruption of the Hoxb8 gene results in chronic anxiety and pathological overgrooming in mice. Using bilateral intracerebral cell transplantation, we demonstrate that mutant Hoxb8 microglia are causative for both behaviors. Mice contain two microglia lineages, Hoxb8 and non-Hoxb8 microglia. We proposed that the two lineages work as a binary system, in opposition to each other with Hoxb8 microglia functioning to reduce anxiety and grooming (function as brakes), whereas non-Hoxb8 microglia increase the levels of both behaviors (function as accelerators). This model makes a strong, unexpected prediction: mice containing only wild-type canonical non-Hoxb8 microglia should exhibit pathological levels of grooming and anxiety. We demonstrate that this is the case, providing strong support for both microglia functioning as a binary system and for the ‘Accelerator/Brake’ model. Since mice containing only non-Hoxb8 microglia represent mice with a loss of Hoxb8 function due to the absence of Hoxb8 microglia, the more intensive pathology associated with Hoxb8 mutant mice must reflect that mutant mice have both gain and loss of function components. We identify and quantify the relative contribution of each component.