TY - JOUR
T1 - Neutrophil depletion after subarachnoid hemorrhage improves memory via NMDA receptors
AU - Provencio, Jose Javier
AU - Swank, Valerie
AU - Lu, Haiyan
AU - Brunet, Sylvain
AU - Baltan, Selva
AU - Khapre, Rohini V.
AU - Seerapu, Himabindu
AU - Kokiko-Cochran, Olga N.
AU - Lamb, Bruce T.
AU - Ransohoff, Richard M.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
KW - Cerebral vasospasm
KW - Delayed neurological deterioration after subarachnoid hemorrhage
KW - Innate inflammation
KW - Memory deficits
KW - Neutrophils
KW - Subarachnoid hemorrhage
UR - http://www.scopus.com/inward/record.url?scp=84964335880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964335880&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2016.02.007
DO - 10.1016/j.bbi.2016.02.007
M3 - Article
C2 - 26872422
AN - SCOPUS:84964335880
SN - 0889-1591
VL - 54
SP - 233
EP - 242
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -