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.

Hematologic counts as predictors of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

“…The third day after the initial hemorrhage is suggested to host the initial peak of inflammation in human and animal studies. Cerebral spinal fluid neutrophilia on the third day in patients with SAH was an independent predictor of the later development of DCI in a previous study 39 , and depletion of neutrophils three days after SAH in a murine model mitigated tissue inflammation, reversed cerebral vasoconstriction and restored memory mechanisms at day 6 40 . Finally, none of the patients from our cohort developed infections during the seven-day period of observation, minimizing the possibility of observing leukocytosis secondary to bacterial infections.…”

The neutrophil enzyme myeloperoxidase directly modulates neuronal response after subarachnoid hemorrhage, a sterile injury model

“…In our model of sterile brain injury, peripheral depletion of neutrophils impedes the development of spatial memory deficits after SAH 4 . To determine whether neutrophil effector function plays a role in these deficits, mice deficient in the neutrophil effector proteins myeloperoxidase, elastase and NADPH oxidase (that have been previously implicated in neuronal damage after ischemic stroke) 8,10,17 , were tested ( Fig.…”

“…Previous findings from our laboratory demonstrate that SAH leads to delayed cognitive deficits in mice 5 . These deficits are attributed to the loss of long-term potentiation (LTP) in the hippocampus 4 In addition, the mechanism(s) through which MPO's activity affects neurons is not clear.…”

“…However, the cellular and molecular mechanism of action of neutrophils in the CNS is poorly understood. Our laboratory has shown that peripheral neutrophil infiltration leads to the development of cognitive deficits in a murine model of subarachnoid hemorrhage (SAH) due to loss of late long-term potentiation (L-LTP) in hippocampal neurons 4,5 . Interestingly, although SAH neutrophils do not invade the hippocampus, they never-the-less seem to drive neuronal dysfunction 4 .…”

Neutrophils and viral-induced neurologic disease

“…Herz et al [11] have recently demonstrated that CXCR2 antagonization reduced neurological deficits and infarct volumes following middle cerebral artery occlusion and this was associated with reduced neutrophil infiltration into the CNS. Similarly, depletion of neutrophils following subarachnoid hemorrhage was found to improve memory in a model of aneurysmal subarachnoid hemorrhage (SAH) [33]. Additionally, Zenaro et al [49] have demonstrated a role for the adhesion molecule lymphocyte function-associated antigen 1 (LFA-1) in promoting neutrophil accumulation within the CNS and amplifying AD-like pathology in transgenic models of Alzheimer's disease (AD).…”