title: Elimination of Microglia Improves Functional Outcomes Following Extensive Neuronal Loss in the Hippocampus.
abstract: With severe injury or disease, microglia become chronically activated and damage the local brain environment, likely contributing to cognitive decline. We previously discovered that microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for survival in the healthy adult brain, and we have exploited this dependence to determine whether such activated microglia contribute deleteriously to functional recovery following a neuronal lesion. Here, we induced a hippocampal lesion in mice for 25 d via neuronal expression of diphtheria toxin A-chain, producing both a neuroinflammatory reaction and behavioral alterations. Following the 25 d lesion, we administered PLX3397, a CSF1R inhibitor, for 30 d to eliminate microglia. This post-lesion treatment paradigm improved functional recovery on elevated plus maze and Morris water maze, concomitant with reductions in elevated proinflammatory molecules, as well as normalization of lesion-induced alterations in synaptophysin and PSD-95. Further exploration of the effects of microglia on synapses in a second cohort of mice revealed that dendritic spine densities are increased with long-term microglial elimination, providing evidence that microglia shape the synaptic landscape in the adult mouse brain. Furthermore, in these same animals, we determined that microglia play a protective role during lesioning, whereby neuronal loss was potentiated in the absence of these cells. Collectively, we demonstrate that microglia exert beneficial effects during a diphtheria toxin-induced neuronal lesion, but impede recovery following insult.
  
  
  CONCLUSIONS
  It remains unknown to what degree, and by what mechanisms, chronically activated microglia contribute to cognitive deficits associated with brain insults. We induced a genetic neuronal lesion in mice for 25 d and found activated microglia to increase inflammation, alter synaptic surrogates, and impede behavioral recovery. These lesion-associated deficits were ameliorated with subsequent microglial elimination, underscoring the importance of developing therapeutics aimed at eliminating/modulating chronic microglial activation. Additionally, we found long-term microglial depletion globally increases dendritic spines by ∼35% in the adult brain, indicating that microglia continue to sculpt the synaptic landscape in the postdevelopmental brain under homeostatic conditions. Microglial manipulation can therefore be used to investigate the utility of increasing dendritic spine numbers in postnatal conditions displaying synaptic aberrations.
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Rice
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Spangenberg
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Hana
authors.initials: H
authors.lastname: Yamate-Morgan
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Rajan P S
authors.initials: RP
authors.lastname: Arora
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Michael X
authors.identifier: http://orcid.org/0000-0003-4165-154X
authors.initials: MX
authors.lastname: Hernandez
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Tenner
authors.affiliation: Plexxikon, Inc., Berkeley, California 94710.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California 92697, and kngreen@uci.edu.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001526:Behavioral Symptoms / Q000209:etiology; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D011758:Pyrroles; D016708:Synaptophysin; C000600259:pexidartinib; D010751:Phosphopyruvate Hydratase; D004318:Doxycycline
keywords: behavior; glia; inflammation; lesion; spines; synapse