Global ischemia caused by a heart attack results in motor, cognitive, memory deficits in the many patients who survive. Purkinje cells in the cerebellum are particularly sensitive to ischemic injury but few studies have focused on this population of neurons despite their key role in coordinating motor function. Purkinje cells undergo a late developmental onset of NMDA receptor expression at 4-6 weeks after birth. This suggests that glutamate signaling, plasticity and excitotoxicity mechanisms may be fundamentally different in juveniles versus adults. Using our laboratories pediatric and adult mouse models of cardiac arrest and cardiopulmonary resuscitation (CA/CPR) this proposal will test the hypothesis that injury mechanism in adult and pediatric mice converge on CAMKII activation to mediate injury. To address excitotoxicity mechanisms following CA/CPR, glutamate receptor antagonists and CAMKII inhibitors will be administered and Purkinje cell loss will be examined. This proposal will also examine the functional consequences of global cerebral ischemia on Purkinje cell excitability and motor coordination deficits. It will also examine whether plasticity and cerebellar dependent learning are impaired. Experiments outlined in this proposal will use electrophysiology, live cell imaging and neurobehavioral testing to investigate changes in the adult and juvenile after CA/CPR. Results obtained will further our understanding of injury mechanisms in Purkinje cells and help to identify therapeutic targets to improve motor coordination deficits after heart attack.
This research proposal aims to examine developmental changes in injury mechanisms and functional consequences of cerebellar injury in mice that have undergone transient global ischemia due to cardiac arrest/resuscitation. These studies will improve our understanding in the mechanisms that contribute to neuronal damage that result in motor coordination deficits.
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| Quillinan, Nidia; Deng, Guiying; Shimizu, Kaori et al. (2017) Long-term depression in Purkinje neurons is persistently impaired following cardiac arrest and cardiopulmonary resuscitation in mice. J Cereb Blood Flow Metab 37:3053-3064 |
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| Shimizu, Takeru; Dietz, Robert M; Cruz-Torres, Ivelisse et al. (2016) Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia. Exp Neurol 283:151-6 |
