Stroke is the leading cause of death and number one cause of disability in the United States. The objective of this proposal is to identify the cellular mechanisms of electrophysiological changes associated with neuronal damage in striatum after transient cerebral ischemia. Spiny neurons in striatum are highly vulnerable to cerebral ischemia. The current knowledge about the pathogenesis of neuronal injury after ischemia is mainly derived from studies on hippocampal neurons. However, the ischemic threshold and time course of cell death in striatum are different from 'those in hippocampus. The neurophysiological changes of striatal neurons following ischemia and their relationship to neuronal damage might not be the same as those of hippocampal neurons. Accumulating evidence has indicated that dopamine aggravates neuronal injury in striatum. Using intracellular recording and staining techniques in vivo, recent studies from this laboratory have demonstrated the depression of inhibitory postsynaptic potentials (IPSPs) in spiny neurons after severe cerebral ischemia. The depression of IPSPs may trigger the excitotoxic neuronal injury in striatum after ischemia. The working hypothesis of this proposal is that the depression of inhibitory components in spiny neurons after ischemia is due to the reduction of inhibitory inputs and dopamine facilitates this process by modulating the synaptic transmission and potassium conductance of striatal neurons. Using in vitro and in vivo preparations, the experiments in this proposal are designed to determine: 1) How excitatory and inhibitory synaptic transmission in spiny neurons and interneurons are altered after ischemia? 2) How dopamine modulation influences these changes? 3) Whether application of dopamine receptor agonists or antagonists protects striatal neurons after transient forebrain ischemia? The specific aims of the proposed experiments are: 1. To compare the excitatory and inhibitory inputs to spiny neurons before and after transient forebrain ischemia. 2. To examine the changes of excitatory inputs and excitability of interneurons after ischemia. 3. To investigate the effects of dopamine modulation on synaptic transmission and potassium currents in spiny neurons after ischemia. 4. To evaluate the protection of dopamine receptor agonist or antagonist on striatal neurons after transient forebrain ischemia. The results of these studies will improve understanding of mechanisms of neuronal injury upon resuscitation following cardiac arrest and provide bases for developing therapeutical interventions for stroke patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038053-08
Application #
6986046
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Hicks, Ramona R
Project Start
1998-04-01
Project End
2007-12-31
Budget Start
2006-01-01
Budget End
2007-12-31
Support Year
8
Fiscal Year
2006
Total Cost
$209,422
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Li, Y; Lei, Z; Xu, Z C (2009) Enhancement of inhibitory synaptic transmission in large aspiny neurons after transient cerebral ischemia. Neuroscience 159:670-81
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Deng, Ping; Pang, Zhi-Ping; Lei, Zhigang et al. (2009) Excitatory roles of protein kinase C in striatal cholinergic interneurons. J Neurophysiol 102:2453-61
Zhang, Yuchun; Deng, Ping; Ruan, Yiwen et al. (2008) Dopamine D1-like receptors depress excitatory synaptic transmissions in striatal neurons after transient forebrain ischemia. Stroke 39:2370-6
Deng, Ping; Zhang, Yuchun; Xu, Zao C (2008) Inhibition of Ih in striatal cholinergic interneurons early after transient forebrain ischemia. J Cereb Blood Flow Metab 28:939-47
Lei, Zhigang; Deng, Ping; Xu, Zao C (2008) Regulation of Kv4.2 channels by glutamate in cultured hippocampal neurons. J Neurochem 106:182-92
Deng, Ping; Zhang, Yuchun; Xu, Zao C (2007) Involvement of I(h) in dopamine modulation of tonic firing in striatal cholinergic interneurons. J Neurosci 27:3148-56
Ruan, Yi-Wen; Zou, Bende; Fan, Yuan et al. (2007) Morphological heterogeneity of CA1 pyramidal neurons in response to ischemia. J Neurosci Res 85:193-204

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