title: Region-specific role for GluN2B-containing NMDA receptors in injury to Purkinje cells and CA1 neurons following global cerebral ischemia.
abstract: Motor deficits are present in cardiac arrest survivors and injury to cerebellar Purkinje cells (PCs) likely contribute to impairments in motor coordination and post-hypoxic myoclonus. N-Methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity is a well-established mechanism of cell death in several brain regions, but the role of NMDA receptors in PC injury remains understudied. Emerging data in cortical and hippocampal neurons indicate that the GluN2A-containing NMDA receptors signal to improve cell survival and GluN2B-containing receptors contribute to neuronal injury. This study compared neuronal injury in the hippocampal CA1 region to that in PCs and investigated the role of NMDA receptors in PC injury in our mouse model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Analysis of cell density demonstrated a 24% loss of PCs within 24 h after 8 min CA/CPR and injury stabilized to 33% by 7 days. The subunit promiscuous NMDA receptor antagonist MK-801 protected both CA1 neurons and PCs from ischemic injury following CA/CPR, demonstrating a role for NMDA receptor activation in injury to both brain regions. In contrast, the GluN2B antagonist, Co 101244, had no effect on PC loss while protecting against injury in the CA1 region. These data indicate that ischemic injury to cerebellar PCs progresses via different cell death mechanisms compared to hippocampal CA1 neurons.
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States. Electronic address: nidia.quillinan@ucdenver.edu.
authors.forename: N
authors.initials: N
authors.lastname: Quillinan
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: H
authors.initials: H
authors.lastname: Grewal
authors.affiliation: Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: G
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: J C
authors.initials: JC
authors.lastname: Yonchek
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: F
authors.initials: F
authors.lastname: Strnad
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States; Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: R J
authors.initials: RJ
authors.lastname: Traystman
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States; Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States.
authors.forename: P S
authors.initials: PS
authors.lastname: Herson
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D064026:Calbindins / Q000378:metabolism; D016887:Cardiopulmonary Resuscitation; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006323:Heart Arrest; D008297:Male; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D064026:Calbindins; D018691:Excitatory Amino Acid Antagonists; C121673:Gprin1 protein, mouse; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; C120799:PD 174494
keywords: NMDA; Purkinje cells; cardiac arrest; excitotoxicity; global ischemia