title: Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors.
abstract: Cognitive deficits after aneurysmal subarachnoid hemorrhage (SAH) are common and disabling. Patients who experience delayed deterioration associated with vasospasm are likely to have cognitive deficits, particularly problems with executive function, verbal and spatial memory. Here, we report neurophysiological and pathological mechanisms underlying behavioral deficits in a murine model of SAH. On tests of spatial memory, animals with SAH performed worse than sham animals in the first week and one month after SAH suggesting a prolonged injury. Between three and six days after experimental hemorrhage, mice demonstrated loss of late long-term potentiation (L-LTP) due to dysfunction of the NMDA receptor. Suppression of innate immune cell activation prevents delayed vasospasm after murine SAH. We therefore explored the role of neutrophil-mediated innate inflammation on memory deficits after SAH. Depletion of neutrophils three days after SAH mitigates tissue inflammation, reverses cerebral vasoconstriction in the middle cerebral artery, and rescues L-LTP dysfunction at day 6. Spatial memory deficits in both the short and long-term are improved and associated with a shift of NMDA receptor subunit composition toward a memory sparing phenotype. This work supports further investigating suppression of innate immunity after SAH as a target for preventative therapies in SAH.
authors.affiliation: Neuroinflammation Research Center, Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA; Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA; Department of Neurology and Neuroscience, Brain Immunology and Glia Center, University of Virginia, PO Box 800394, Charlottesville, VA 22908, USA. Electronic address: jp3b@virginia.edu.
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Provencio
authors.affiliation: Neuroinflammation Research Center, Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Swank
authors.affiliation: Neuroinflammation Research Center, Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Lu
authors.affiliation: Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brunet
authors.affiliation: Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Selva
authors.initials: S
authors.lastname: Baltan
authors.affiliation: Neuroinflammation Research Center, Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Rohini V
authors.initials: RV
authors.lastname: Khapre
authors.affiliation: Neuroinflammation Research Center, Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Himabindu
authors.initials: H
authors.lastname: Seerapu
authors.affiliation: Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Neuroinflammation Research Center, Neuroscience, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
mesh_terms: D000818:Animals; D007113:Immunity, Innate / Q000276:immunology; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013345:Subarachnoid Hemorrhage / Q000097:blood / Q000628:therapy*; D020301:Vasospasm, Intracranial / Q000628:therapy
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate
keywords: Cerebral vasospasm; Delayed neurological deterioration after subarachnoid hemorrhage; Innate inflammation; Memory deficits; Neutrophils; Subarachnoid hemorrhage