The long-term goal of this project is to understand how neurons of the cerebral cortex of mammals including ourselves communicate with each other by means of synaptic inhibition, in the belief that such basic understanding will lead to pharmacological tools that will therapeutically enhance such inhibitory processes in pathological conditions such as certain of the epilepsies. To approach this goal, we have examined in depth a non-classic form of inhibition that, unlike the better known type, is not mediated by GABAa receptors, and depends upon a potassium rather than chloride conductance. Most recently, we have discovered that the potassium conductance of this inhibitory effect (the late IPSP), as well as that activated by the GABAb agonist baclofen, is controlled by a GTP-binding protein (G-protein) of the sort that is a substrate for pertussis toxin. We therefore propose to use this agonist in a model system of cultured hippocampal neurons to begin to dissect the molecular control of the late IPSP conductance. We will use the single electrode voltage clamp to make necessary current measurements in neurons in the hippocampal slice, and whole cell patch clamp of cultured hippocampal neurons to make the quantitative intraneuronal injections and current recordings called for in Specific Aims II, III and V. Importantly, these studies are complemented by biochemical assays of molecular elements that underly this response. Specifically, we propose to: 1) further verify GABA, and to test somatostatin (the other presently remaining candidate as transmitter of the late IPSP) as transmitters of the late IPSP and as appropriate agonists with which to model the late IPSP conductance in culture; 2) to evaluate a model of the late IPSP conductance with respect to the critical characteristic of G- protein control, that is, to determine whether the potassium conductance that is elicited by GABAb agonists in cultured hippocampal neurons depends upon a pertussis toxin sensitive G- protein; 3) to specify, by examination of this model, the particular G-protein that controls this conductance, and the subunit of this protein that is responsible for its action; 4) to determine whether some of the molecular components of the late IPSP and the late IPSC itself are present in mammals other than the presently used rodent models; and 5) to further explicate the molecular organization of the control of the late IPSP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021713-08
Application #
3403158
Study Section
Neurology A Study Section (NEUA)
Project Start
1985-07-01
Project End
1993-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
8
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Al-Dahan, M I; Jalilian Tehrani, M H; Thalmann, R H (1999) Regulation of cyclic AMP level by progesterone in ovariectomized rat neocortex. Brain Res 824:258-66
al-Dahan, M I; Thalmann, R H (1996) Progesterone regulates gamma-aminobutyric acid B (GABAB) receptors in the neocortex of female rats. Brain Res 727:40-8
al-Dahan, M I; Jalilian Tehrani, M H; Thalmann, R H (1994) Regulation of gamma-aminobutyric acidB (GABAB) receptors in cerebral cortex during the estrous cycle. Brain Res 640:33-9
al-Dahan, M I; Tehrani, M H; Thalmann, R H (1990) Effect of 2-hydroxy-saclofen, an antagonist of GABAB action, upon the binding of baclofen and other receptor ligands in rat cerebrum. Brain Res 526:308-12
Al-Dahan, M I; Thalmann, R H (1989) Effects of dihydropyridine calcium channel ligands on rat brain gamma-aminobutyric acidB receptors. J Neurochem 53:982-5
al-Dahan, M I; Thalmann, R H (1989) Effect of guanosine 5'-O-(3-thiotriphosphate) and calcium on gamma-aminobutyric acidB binding as a function of postnatal development. J Neurochem 52:313-6
Thalmann, R H (1988) Evidence that guanosine triphosphate (GTP)-binding proteins control a synaptic response in brain: effect of pertussis toxin and GTP gamma S on the late inhibitory postsynaptic potential of hippocampal CA3 neurons. J Neurosci 8:4589-602
Thalmann, R H (1988) Blockade of a late inhibitory postsynaptic potential in hippocampal CA3 neurons in vitro reveals a late depolarizing potential that is augmented by pentobarbital. Neurosci Lett 95:155-60
Thalmann, R H (1987) Pertussis toxin blocks a late inhibitory postsynaptic potential in hippocampal CA3 neurons. Neurosci Lett 82:41-6
Hablitz, J J; Thalmann, R H (1987) Conductance changes underlying a late synaptic hyperpolarization in hippocampal CA3 neurons. J Neurophysiol 58:160-79

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