title: Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain.
abstract: Microglia actively survey the brain microenvironment and play essential roles in sculpting synaptic connections during brain development. While microglial functions in the adult brain are less clear, activated microglia can closely appose neuronal cell bodies and displace axosomatic presynaptic terminals. Microglia-mediated stripping of presynaptic terminals is considered neuroprotective, but the cellular and molecular mechanisms are poorly defined. Using 3D electron microscopy, we demonstrate that activated microglia displace inhibitory presynaptic terminals from cortical neurons in adult mice. Electrophysiological recordings further establish that the reduction in inhibitory GABAergic synapses increased synchronized firing of cortical neurons in γ-frequency band. Increased neuronal activity results in the calcium-mediated activation of CaM kinase IV, phosphorylation of CREB, increased expression of antiapoptotic and neurotrophic molecules and reduced apoptosis of cortical neurons following injury. These results indicate that activated microglia can protect the adult brain by migrating to inhibitory synapses and displacing them from cortical neurons.
authors.affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2].
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2].
authors.forename: Walid
authors.initials: W
authors.lastname: Jalabi
authors.affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Park
authors.affiliation: 1] Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Center for Neurological Restoration, Neurological Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Gale
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: Kidd
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Rodica
authors.initials: R
authors.lastname: Bernatowicz
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Gossman
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Chen
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Dutta
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D021621:Imaging, Three-Dimensional; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017729:Presynaptic Terminals / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D008070:Lipopolysaccharides; D005680:gamma-Aminobutyric Acid; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4