The overall objective of the proposed research is to contribute to our understanding of how intracellular Ca2+ regulates the excitability of hippocampal cells. Our interest in this issue is prompted by three recent developments. First, results were obtained showing that NMDA or glutamate, a presumed excitatory neurotransmitters in the hippocampus, caused sustained, significant increases of intracellular Ca2+ in isolated adult hippocampal cells. Secondly, it was discovered that the GABAA receptors in the hippocampal cells can no longer be activated by the ligand when intracellular Ca2+ increased beyond 5x10-6M. This latter finding is particularly interesting since previous data show that a blockade of inhibition mediated by GABAA receptors can led to epileptiform discharge in the hippocampus. Thirdly, we have succeeded in developing a recording system which allowed the changing of the intracellular contents during whole cell recording using isolated hippocampal cells. This technical advancement enables one to directly address questions regarding intracellular function of Ca2+. Proposed experiments will be carried out using acutely dissociated cells from the hippocampus of adult guinea-pigs. The specific objectives are: (1) to examine the role of intracellular Ca2+ in controlling the resting potential of the neurons. Experiments will characterize ionic currents activated by increases in Ca2+ when cells are voltage-clamped at their resting potential. The ionic basis and pharmacology of the currents will be studied. (2) To define the modulatory role of intracellular Ca2+ on voltage(V)-gated Ca2+ and K+ currents and (3) To compare the actions of elevated intracellular Ca2+ resulting from intracellular perfusion with that caused by entry through V- or ligand- gated channels. The study thus directly evaluates the control of cellular and perhaps circuitry (via GABAA receptor modulation) excitation by intracellular Ca2+. The results will contribute to our understanding of the generation and control of normal and abnormal activities in the hippocampus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024682-07
Application #
3409494
Study Section
Neurology A Study Section (NEUA)
Project Start
1987-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Suny Downstate Medical Center
Department
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Chen, Q X; Perkins, K L; Wong, R K (1998) Zn2+ blocks the NMDA- and Ca2+ -triggered postexposure current ipe in hippocampal pyramidal cells. J Neurophysiol 79:1124-6
Chen, Q X; Perkins, K L; Choi, D W et al. (1997) Secondary activation of a cation conductance is responsible for NMDA toxicity in acutely isolated hippocampal neurons. J Neurosci 17:4032-6
Fan, S H; Wong, R K (1996) Selective expression of transient outward currents in different types of acutely isolated hippocampal interneurons. J Neurophysiol 76:3563-7
Stewart, M; Wong, R K (1995) A method allowing intracellular and extracellular single-unit recordings from brain slices in the grease-gap chamber. J Neurosci Methods 58:17-24
Celentano, J J; Wong, R K (1994) Multiphasic desensitization of the GABAA receptor in outside-out patches. Biophys J 66:1039-50
Fan, S; Stewart, M; Wong, R K (1994) Differences in voltage-dependent sodium currents exhibited by superficial and deep layer neurons of guinea pig entorhinal cortex. J Neurophysiol 71:1986-91
Stewart, M; Wong, R K (1993) Intrinsic properties and evoked responses of guinea pig subicular neurons in vitro. J Neurophysiol 70:232-45
Wong, R K; Stewart, M (1992) Different firing patterns generated in dendrites and somata of CA1 pyramidal neurones in guinea-pig hippocampus. J Physiol 457:675-87
Chen, Q X; Wong, R K (1991) Intracellular Ca2+ suppressed a transient potassium current in hippocampal neurons. J Neurosci 11:337-43
Thompson, S M; Wong, R K (1991) Development of calcium current subtypes in isolated rat hippocampal pyramidal cells. J Physiol 439:671-89

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