Genetic Mutation of GluN2B Protects Brain Cells Against Stroke Damages

• DOI: 10.1007/s12035-017-0562-y
• Publication Date: 2017-04-29T02:50:52Z
• Authors: Na Tang; Jianhua Wu; Houze Zhu; Honglin Yan; Yu Guo; You Cai; Huanhuan Yan; Yan Shi; Shu Shu; Lei Pei; Youming Lu
• Keywords: Male; Neurons; 0301 basic medicine; Behavior, Animal; Brain; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Brain Ischemia; Mice, Inbred C57BL; Stroke; Death-Associated Protein Kinases; Mice, Neurologic Mutants; 03 medical and health sciences; Mutation; Animals; Calcium; Ion Channel Gating

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 Ca2+ influx directly through the receptor-gated ion channels which leads to Ca2+ 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.