Genetic Mutation of GluN2B Protects Brain Cells Against Stroke Damages

• Published in: Molecular neurobiology 2018-04, Vol.55 (4), p.2979-2990
• Main Authors: Tang, Na, Wu, Jianhua, Zhu, Houze, Yan, Honglin, Guo, Yu, Cai, You, Yan, Huanhuan, Shi, Yan, Shu, Shu, Pei, Lei, Lu, Youming
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Behavior, Animal; Biomedical and Life Sciences; Biomedicine; Brain - pathology; Brain Ischemia - metabolism; Brain Ischemia - pathology; Calcium - metabolism; Calcium channels; Calcium influx; Cell Biology; Channel gating; Clonal deletion; Death-associated protein kinase; Death-Associated Protein Kinases - metabolism; Forebrain; Glutamic acid receptors (ionotropic); Ion Channel Gating; Ion channels; Ischemia; Kinases; Male; Mice; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mutation; Mutation - genetics; N-Methyl-D-aspartic acid receptors; Neurobiology; Neurology; Neurons - metabolism; Neurons - pathology; Neurosciences; Propionic acid; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Rodents; Stroke; Stroke - genetics; Stroke - pathology; Synaptic Transmission; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0562-y

Immediately following ischemia, glutamate accumulates in the extracellular space and results in extensive stimulation of its receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. A large amount of Ca 2+ influx directly through the receptor-gated ion channels which leads to Ca 2+ overload and triggers several downstream lethal reactions. As a result, cell dies via apoptosis or necrosis, or both. Death-associated protein kinase 1 (DAPK1) physically and functionally interacts with the NMDA receptor GluN2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. The goal of this study is to explore an effective strategy in the treatment of stroke with a molecular genetic manipulation to interrupt DAPK1-GluN2B interaction. We generated a mutant strain of mice with the conditional deletion of GluN2B C-terminal tail consisting of amino acids 886–1269 in the forebrain excitatory neurons (the GluN2B mutant mice) and tested the protective effects of this mutation in stroke damages. GluN2B mutation effectively disrupted the DAPK1-GluN2B interaction and inhibited extra-synaptic NMDA receptor currents without affecting synaptic NMDA receptor channel activity in the central neurons. GluN2B mutation protected against stroke damages both in vitro and in vivo and hence improved behavioral performance. Disruption of the DAPK1-GluN2B interaction is therapeutically effective against stroke damages.