Editors' preface: Microglia—A new era dawns

This Special Issue of Glia appears almost precisely 10 years after the last Special Issue devoted to microglia. Given the perspicacity of the Editors-in-Chief that fact is not likely to be coincidental. Having said that, the present volume represents in our view an opportunity to take stock of a remarkable epoch in microglial research, inhale a deep breath, and prepare for wonders yet to come. The first two articles in this issue acknowledge new technologies. Seeger and Peri discuss animal models for studying microglia, emphasizing that the field made major strides by studying the leech, consolidated genetic approaches by using mice, and looks forward to exploiting zebrafish. Implicit in this review is the notion that the greater part of questions about microglial function can now be addressed in vivo, a sea-change in itself. Venneti, LoPresti, and Wiley discuss the clinical progress made and anticipated in using positron emission tomography to image microglia in the intact human brain. Notably, the application of two-photon imaging for microglia in the living experimental specimen is so well established as not to require a separate discussion. Schafer, Lehrman, and Stevens dive into functional studies by asking why microglia are required so early in development and find an unexpected answer related to synapse maturation. As it proceeds and matures, this exciting and burgeoning field of investigation also possesses high potential for clarifying contributions of microglia to neurodevelopmental disorders and to neurodegeneration. Linnartz and Neumann show how the cell-cell contracts between microglia and neurons (required for monitoring and modulating synapses) engage inhibitory or inflammatory signaling contingent on the intact sialic acid ‘‘cap" on neuronal glycoproteins. Koizumi, Ohsawa, Inoue, and Kohsaka discuss the important topic of purinergic signaling to microglia and introduce the attractive concept they term ‘‘modal shifts" in the dynamic microglial response to purinergic mediators. Tsuda, Beggs, Salter, and Inoue extend the theme of purinergic signaling in their treatment of the role(s) of microglia in intractable chronic pain. Blank and Prinz bring the concepts of microglia-mediated neuromodulation and maintenance of homeostasis to the bedside in their account of microglia in neuropsychiatric and developmental disorders, a topic which received widespread attention this year with proof-of-principle research conducted in a Rett’s Syndrome mouse model (Nature 2012;484:105–109). Cunningham discusses bench-to-bedside research showing how systemic inflammation albeit relatively mild can stimulate microglia to heightened inflammatory states and worsen both experimental and clinical neurodegeneration. Ponomarev and Weiner summarize microRNAs, a recent topic applicable to virtually all biological processes. Their research pioneered the application of this class of regulators to microglia and promises to help clarify the complex nascent field of differential stimulus-dependent gene expression by microglia in vivo. Saijo, Crotti and Glass consider the intricate mechanisms by which nuclear hormone receptors trans-regulate programs of gene transcription, which underlie both microglial activation and subsequent return to homeostatic ’surveillant’ mode. Finally, we come to the origin questions: where do microglia come from and how are they maintained in the brain under conditions of homeostasis? Perdiguero, Schulz, and Geissmann provide unique and novel perspective on the place of microglia in the universe of myeloid cells. Greter and Merad delineate developmental origins of microglia and ask how this knowledge can inform therapeutic attempts to engineer hematopoietic cells to engraft the disordered brain for patient benefit. Together, these reviews encapsulate our present understanding of microglia and