A Novel Ionic Mechanism of Ischemic Neuronal Injury

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DESCRIPTION (provided by applicant): Effective treatment for stroke is limited largely by the fact that the underlying mechanisms of neuronal death caused by cerebral ischemia are still unclear. This proposal will investigate the ionic mechanisms of ischemic neuronal injury. Transient cerebral ischemia causes selective neuronal death in certain brain regions, including the neostriatum, which is fundamental to sensorimotor learning, movement control and cognitive functions. Protecting striatal neurons against ischemia will improve the recovery of striatum-mediated functions after stroke. Studies have shown that increase of neuronal excitability and disruption of intracellular ion homeostasis are critical for neuronal injury after ischemia. Hyperpolarization-activated cation current (Ih) mediates influx of Na+ and K+, and plays critical roles in controlling neuronal excitability. Most of previous studies have focused on the excitotoxicity and depolarization-activated ion channels, and indicate that post-ischemic depolarization may contribute to cell death, and that hyperpolarization may be involved in neuroprotection. However, active Ih during hyperpolarization in striatal neurons may be associated with ischemic neuronal injury. Indeed, we have found that transient forebrain ischemia induces an expression of functional Ih in ischemia-vulnerable spiny neurons in the neostriatum, which is absent under control conditions. Meanwhile, Ih in ischemia-resistant striatal cholinergic interneurons is inhibited after ischemia. Most importantly, our preliminary data have shown that blocking Ih protects striatal neurons against ischemia. We hypothesize that upregulation of functional Ih contributes to ischemic neuronal death in the neostriatum. In this project, experiments are designed to investigate how Ih in striatal neurons is altered after ischemia, what are the underlying mechanisms, and what are the relations of Ih change with ischemic neuronal death. The temporal changes of Ih in striatal neurons following transient forebrain ischemia will be characterized using electrophysiological recording. To investigate the underlying mechanisms of Ih changes, the modulation of Ih by cyclic AMP and membrane phospholipids (PIP2) will be compared before and after ischemia. In addition, alterations of Ih channel interacting proteins (TRIP8b), which profoundly regulate Ih function, will be examined. Finally, the involvement of specific Ih channel subunits will be identified in ischemia in vivo models. This project may provide novel strategies to protect neurons against ischemic insults.