IONIC HOMEOSTASIS AND SEIZURE REGULATION

Summary

Principal Investigator: JOHN WILLIAM SWANN
Abstract: 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.
Funding Period: 2000-04-01 - 2010-07-30
more information: NIH RePORT

Top Publications

  1. pmc Seizures in early life suppress hippocampal dendrite growth while impairing spatial learning
    Masataka Nishimura
    The Cain Foundation Laboratories, The Jan and Dan Duncan Neurological Research Institute, USA
    Neurobiol Dis 44:205-14. 2011
  2. ncbi Anticonvulsant activity of ginseng on seizures induced by chemical convulsants
    Xiao yuan Lian
    Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA
    Epilepsia 46:15-22. 2005
  3. ncbi Protective effects of ginseng components in a rodent model of neurodegeneration
    Xiao yuan Lian
    Department of Pharmacology, Baylor College of Medicine, Houston 77030, USA
    Ann Neurol 57:642-8. 2005
  4. pmc Regulation of extracellular calcium in the hippocampus in vivo during epileptiform activity--role of astrocytes
    Janet L Stringer
    Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
    Epilepsy Res 74:155-62. 2007
  5. ncbi Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats
    Xiao yuan Lian
    Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurosci 27:12007-11. 2007
  6. pmc Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats
    Kaiping Xu
    Department of Pharmacology, Baylor College of Medicine, United States
    Pharmacol Res 57:234-8. 2008
  7. pmc Antioxidants and free radical scavengers do not consistently delay seizure onset in animal models of acute seizures
    Kaiping Xu
    Baylor College of Medicine, Houston, TX 77030, USA
    Epilepsy Behav 13:77-82. 2008
  8. pmc Oral administration of fructose-1,6-diphosphate has anticonvulsant activity
    Xiao yuan Lian
    Baylor College of Medicine, Houston TX, USA
    Neurosci Lett 446:75-7. 2008
  9. pmc Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphate
    Janet L Stringer
    Baylor College of Medicine, Houston, Texas, USA
    Epilepsia 49:101-3. 2008

Scientific Experts

  • Janet L Stringer
  • Xiao yuan Lian
  • Kaiping Xu
  • Masataka Nishimura
  • John W Swann
  • Xue Gu
  • Firdous A Khan
  • Zhi Zhen Zhang
  • Zhizhen Zhang

Detail Information

Publications9

  1. pmc Seizures in early life suppress hippocampal dendrite growth while impairing spatial learning
    Masataka Nishimura
    The Cain Foundation Laboratories, The Jan and Dan Duncan Neurological Research Institute, USA
    Neurobiol Dis 44:205-14. 2011
    ..Our results suggest that the recurring seizures of intractable childhood epilepsy contribute to associated learning and memory deficits by suppressing dendrite growth...
  2. ncbi Anticonvulsant activity of ginseng on seizures induced by chemical convulsants
    Xiao yuan Lian
    Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA
    Epilepsia 46:15-22. 2005
    ..To test the anticonvulsant activity of three preparations of American ginseng: whole root extract, whole leaves/stems extract, and a partially purified extract that concentrates the Rb ginsenosides (Rb extract)...
  3. ncbi Protective effects of ginseng components in a rodent model of neurodegeneration
    Xiao yuan Lian
    Department of Pharmacology, Baylor College of Medicine, Houston 77030, USA
    Ann Neurol 57:642-8. 2005
    ..The results demonstrate that some of the ginsenosides have neuroprotective activity, and that a partial purification of whole ginseng to concentrate the neuroprotective components may have utility as a neuroprotective agent...
  4. pmc Regulation of extracellular calcium in the hippocampus in vivo during epileptiform activity--role of astrocytes
    Janet L Stringer
    Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
    Epilepsy Res 74:155-62. 2007
    ..The results suggest that maximal decreases in [Ca(2+)](o) occur in the hippocampus in response to burst firing of neurons and that astrocytes play a minimal role in the regulation of [Ca(2+)](o) during epileptiform activity...
  5. ncbi Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats
    Xiao yuan Lian
    Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurosci 27:12007-11. 2007
    ..These data demonstrate that F1,6BP has significant anticonvulsant efficacy...
  6. pmc Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats
    Kaiping Xu
    Department of Pharmacology, Baylor College of Medicine, United States
    Pharmacol Res 57:234-8. 2008
    ..Finally, the experiments demonstrate a significant increase in brain levels of FDP after oral administration. These data suggest that an oral formulation of FDP might be developed for treatment of neurological disease...
  7. pmc Antioxidants and free radical scavengers do not consistently delay seizure onset in animal models of acute seizures
    Kaiping Xu
    Baylor College of Medicine, Houston, TX 77030, USA
    Epilepsy Behav 13:77-82. 2008
    ..The lack of consistent anticonvulsant effect suggests that the antioxidant activity of the herbal preparations cannot account for the delay in seizure onset...
  8. pmc Oral administration of fructose-1,6-diphosphate has anticonvulsant activity
    Xiao yuan Lian
    Baylor College of Medicine, Houston TX, USA
    Neurosci Lett 446:75-7. 2008
    ..These experiments suggest that oral administration of FDP may have utility in the treatment of partial or generalized convulsive seizure disorders, but not absence seizures...
  9. pmc Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphate
    Janet L Stringer
    Baylor College of Medicine, Houston, Texas, USA
    Epilepsia 49:101-3. 2008
    ....