Cardiac arrest and stroke are major causes of death and disability and often result in neurological impairment. Neural damage is often heterogeneous as some regions of the brain are more vulnerable to the hypoxia and ischemia (H-I) caused by these insults. The cerebellum is such a region and hypoxic and ischemic events in the cerebellum often result in ataxia and other problems with motor coordination. Neuronal calcium (Ca2+) dysregulation and Ca2+ overload are recognized as causes of cell death following brain H-I. Recently we identified stromal interaction molecules (STIM) as key components of Ca2+ signaling in excitable cells where they activate refilling of Ca2+ stores during repetitive electrical activity. Given an exceptionally high level of STIM1 expression in cerebellar Purkinje neurons and the selective vulnerability of these neurons to damage by H-I, we hypothesize that STIM1 is essential to refill Ca2+ stores and sustain Ca2+ signaling in Purkinje neurons during periods of intense synaptic activity, as occurs with H-I injury; thus, STIM1-SOCE is a critical mediator of the excitotoxic Ca2+ dysregulation and overload that causes Purkinje neuron injury and death. Our goal is to test this hypothesis by determining the fundamental properties and functions of STIM1-SOCE in Purkinje neurons during physiological and H-I conditions. For this purpose, we will carry out Ca2+ imaging, electrophysiological, morphological, and biochemical studies of cerebellar properties and function, with a focus on Purkinje neurons, in acute brain slices (Aims 1 and 2) and Purkinje neurons and other vulnerable neurons in vivo (Aim 3) in WT and STIM1 mutant mice to address the following specific aims: 1) Determine the fundamental properties and physiological functions of STIM1-dependent SOCE in cerebellar Purkinje cells, 2) Determine the contribution of STIM1-SOCE to H-I induced injury and death of Purkinje neurons in vitro, and 3) Determine the contribution of STIM1 to the neuronal damage and motor and cognitive dysfunction produced by global ischemia in vivo. These studies will begin to elucidate the role of STIM1-SOCE in Purkinje cell Ca2+ homeostasis and cerebellar function under normal physiological conditions and the contribution of STIM1-SOCE to Ca2+ overload, neuronal death, and neurological dysfunction that is produced by hypoxia and ischemia in the cerebellum and other brain regions.
Cardiac arrest and stroke are important causes of disability. Deprivation of oxygen alters brain signaling leading to neuronal death. The importance of Ca2+ dysregulation is well established during hypoxia and ischemic damage. We will determine how Ca2+ signaling from stromal interaction molecule 1 (STIM1) influence H-I injury.
| Zhang, Hengtao; Sun, Albert Y; Kim, Jong J et al. (2015) STIM1-Ca2+ signaling modulates automaticity of the mouse sinoatrial node. Proc Natl Acad Sci U S A 112:E5618-27 |
| Zhao, Guiling; Li, Tianyu; Brochet, Didier X P et al. (2015) STIM1 enhances SR Ca2+ content through binding phospholamban in rat ventricular myocytes. Proc Natl Acad Sci U S A 112:E4792-801 |
