Layer V cortical neurons require microglial support for survival during postnatal development

• Published in: Nature neuroscience Vol. 16; no. 5; pp. 543 - 551
• Main Authors: Ueno, Masaki, Fujita, Yuki, Tanaka, Tatsuhide, Nakamura, Yuka, Kikuta, Junichi, Ishii, Masaru, Yamashita, Toshihide
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2013; Nature Publishing Group
• Subjects: 631/136; 631/378/1686; 631/378/1934; 631/378/2571/1696; 631/378/2596/1953; Animal Genetics and Genomics; Animals; Animals, Newborn; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Behavioral Sciences; Biological Techniques; Biomedicine; Brain; Brain research; Calcium-Binding Proteins - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; CD11b Antigen - metabolism; Cell death; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; Coculture Techniques; CX3C Chemokine Receptor 1; Diphtheria Toxin - pharmacology; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Fetus; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - physiology; Growth; Health aspects; Humans; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Kinases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins - metabolism; Microglia - drug effects; Microglia - physiology; Morphology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neuroglia; Neurons; Neurons - drug effects; Neurons - physiology; Neurosciences; Physiological aspects; Receptors, Chemokine - deficiency; Visual Cortex - cytology; Visual Cortex - embryology; Visual Cortex - growth & development; Japan
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.3358

In this study, the authors show that layer V projection neurons require the presence of subcortical CX3CR1-positive microglia for survival. IGF1 secretion from these microglia appears to be necessary for this trophic effect. Inhibition of the microglial cell activation abrogates IGF1 secretion and compromises neuronal survival. Neurons require trophic support during neural circuit formation; however, how the cellular milieu contributes to neuronal survival remains unclear. We found that layer V cortical neurons require support from microglia for survival during postnatal development. Specifically, we found that microglia accumulated close to the subcerebral and callosal projection axons in the postnatal brain. Inactivation of microglia by minocycline treatment or transient ablation of microglia in CD11b-DTR transgenic mice led to increased apoptosis, specifically in layer V subcerebral and callosal projection neurons. CX3CR1 in microglia was required for the survival of layer V neurons. Microglia consistently promoted the survival of cortical neurons in vitro . In addition, we identified microglia-derived IGF1 as a trophic factor that maintained neuronal survival. Our results highlight a neuron-glia interaction that is indispensable for network formation during a specific period in the developing brain.