The long-term goal of this research is to understand how neurons become synchronized into seizure discharges and how the brain terminates the synchronized activity. In the last grant period experiments explored the mechanisms underlying regulation of extracellular potassium and how this regulation might influence neuronal excitability and started to examine regulation of pH. Preliminary evidence suggests that the changes in extracellular pH contribute to regulation of neuronal activity and may contribute to the relative seizure sensitivity of brain regions. Preliminary data also suggest that astrocytes play a significant role in regulation of extracellular calcium, thus influencing neuronal excitability and possibly neuronal vulnerability. In this grant period, we will continue to focus on the role of the ionic environment in neuronal synchronization, with an emphasis on pH and calcium. Hypothesis 1 -The regional differences in pH during neuronal activity are due to differences in active acid transporters in the neurons in the region. This will be tested by determining which pH regulatory processes are different in the dentate gyrus compared to CA1, both in vivo and in vitro. Intracellular pH in CA1 will be measured and compared to seizure duration and extracellular pH to determine whether intracellular pH mirrors extracellular pH and whether it contributes to seizure termination in CA1. Anatomical and pharmacological studies will determine which ion transporters are involved in the regulation of pH in the dentate gyrus and CA1, with examination of changes during and after neuronal activity. Hypothesis 2 - Recovery of the extracellular calcium during neuronal activity is due to efflux of calcium from astrocytes. This hypothesis will be tested by determining extracellular calcium changes in CA1 and the dentate gyrus in vivo and in vitro during trains of stimulation. Pharmacological blockers will determine the role of the different voltage-gated calcium channels and the role of calcium released from internal stores. The role of astrocytes in the recovery of extracellular calcium during continued neuronal activity will be tested using glial specific toxins. This hypothesis will be directly tested by measuring changes in intracellular calcium in glial cells and neurons during stimulus trains in hippocampal slices while measuring extracellular calcium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039941-07
Application #
7259432
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Stewart, Randall R
Project Start
2000-04-01
Project End
2010-07-30
Budget Start
2007-07-31
Budget End
2008-07-30
Support Year
7
Fiscal Year
2007
Total Cost
$263,121
Indirect Cost
Name
Baylor College of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Nishimura, Masataka; Gu, Xue; Swann, John W (2011) Seizures in early life suppress hippocampal dendrite growth while impairing spatial learning. Neurobiol Dis 44:205-14
Frost Jr, James D; Lee, Chong L; Hrachovy, Richard A et al. (2011) High frequency EEG activity associated with ictal events in an animal model of infantile spasms. Epilepsia 52:53-62
Stringer, Janet L; Xu, Kaiping (2008) Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphate. Epilepsia 49 Suppl 8:101-3
Xu, Kaiping; Stringer, Janet L (2008) Antioxidants and free radical scavengers do not consistently delay seizure onset in animal models of acute seizures. Epilepsy Behav 13:77-82
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Lian, Xiao-Yuan; Khan, Firdous A; Stringer, Janet L (2007) Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci 27:12007-11
Stringer, Janet L; Mukherjee, Kakali; Xiang, Ting et al. (2007) Regulation of extracellular calcium in the hippocampus in vivo during epileptiform activity--role of astrocytes. Epilepsy Res 74:155-62
Lian, Xiao-Yuan; Zhang, Zhizhen; Stringer, Janet L (2005) Protective effects of ginseng components in a rodent model of neurodegeneration. Ann Neurol 57:642-8
Lian, Xiao-Yuan; Zhang, Zhi-Zhen; Stringer, Janet L (2005) Anticonvulsant activity of ginseng on seizures induced by chemical convulsants. Epilepsia 46:15-22

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