Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain

• Authors: Zhihong Chen, Emory University; Walid Jalabi, Cleveland Clinic; Weiwei Hu, Cleveland Clinic; Hyun-Joo Park, Cleveland Clinic; John T. Gale, Emory University; Grahame J. Kidd, Cleveland Clinic; Rodica Bernatowicz, Cleveland Clinic; Zachary C. Gossman, Cleveland Clinic; Jacqueline T. Chen, Cleveland Clinic; Ranjan Dutta, Cleveland Clinic; Bruce D. Trapp, Cleveland Clinic
• Journal Title: Nature Communications
• Volume: Volume 5, Number 1
• Publisher: Nature Publishing Group: Nature Communications | 2014-07-01, Pages 4486-4486
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/ncomms5486
• Subjects: Health Sciences, Pharmacology; Biology, Neuroscience
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CEREBELLAR GRANULE CELLS; NMDA RECEPTOR; IN-VIVO; ACTIVATION; CNS; TERMINALS; DEATH; LIPOPOLYSACCHARIDE; INFLAMMATION; EXPRESSION

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.