This project will explore how inhibition is controlled in the dentate gyrus of the rat hippocampal slice. There are poorly understood disinhibitory mechanisms in the brain that transiently suppress inhibitory interneuron function. Setting the level of inhibitory neuron function has profound effects on neural plasticity such as long term potentiation, a model of learning, and on paroxysmal activity such as seizures. The dentate gyrus provides an excellent model system for the study of disinhibitory mechanisms because profound transient suppression of recurrent inhibition can be triggered in the dentate by a single conditioning stimulus to the adjacent alveus or stratum lucidum of the hippocampus. This phenomenon will herein be refered to as stimulus induced disinhibition or SID. Previous work in this laboratory has shown that GABAB receptor agonists disinhibit the dentate. The work proposed here will explore the hypothesis that SID in the dentate is due to GABAB mediated inhibition of inhibitory basket cells. In these experiments, recurrent inhibition is evoked in the dentate gyrus of the rat hippocampal slice by stimulation of the mossy fibers (granule cell axons). Inhibition is measured by its effect on the extracellular granule cell population spike triggered by a stimulus to the perforate path. SID is induced by stimulation of alveus or stratum recording methods will be used to study SID in the dentate.
The specific aims are to determine: 1) Whether other GABAB receptor antagonists will block SID and the long, late, presumably GABAB mediated inhibitory postsynaptic potentials in the dentate; 2) If inhibitory postsynaptic potentials in granule cells are suppressed during SID; 3) If SID facilitates long term potentiation of synaptic transmission in the dentate gyrus; 4) If basket cells are inhibited by GABAB inhibitory postsynaptic potentials during SID.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027488-02
Application #
3413772
Study Section
Neurology A Study Section (NEUA)
Project Start
1990-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Koistinaho, J; Sagar, S M (1995) Light-induced c-fos expression in amacrine cells in the rabbit retina. Brain Res Mol Brain Res 29:53-63
Mott, D D; Lewis, D V (1994) The pharmacology and function of central GABAB receptors. Int Rev Neurobiol 36:97-223
Koistinaho, J; Sagar, S M (1994) Localization of protein kinase C subspecies in the rabbit retina. Neurosci Lett 177:15-8
Sharp, F R; Hisanaga, K; Sagar, S M (1993) NMDA receptor blockade prevents translation, but not transcription, of the c-fos gene following stimulation with multiple extracellular signals in cultured cortical neurons: implications for plasticity and molecular memory. NIDA Res Monogr 125:172-80
Sharp, F R; Sagar, S M; Swanson, R A (1993) Metabolic mapping with cellular resolution: c-fos vs. 2-deoxyglucose. Crit Rev Neurobiol 7:205-28
Morrisett, R A; Lewis, D V; Swartzwelder, H S et al. (1993) Antiepileptic effects of GABAb receptor activation in area CA3 of rat hippocampus. Brain Res 600:235-42
Koistinaho, J; Hicks, K J; Sagar, S M (1993) Tetrodotoxin enhances light-induced c-fos gene expression in the rabbit retina. Brain Res Mol Brain Res 17:179-83
Koistinaho, J; Hicks, K J; Sagar, S M (1993) Long-term induction of c-jun mRNA and Jun protein in rabbit retinal ganglion cells following axotomy or colchicine treatment. J Neurosci Res 34:250-5
Sagar, S M; Sharp, F R (1993) Early response genes as markers of neuronal activity and growth factor action. Adv Neurol 59:273-84
Mott, D D; Xie, C W; Wilson, W A et al. (1993) GABAB autoreceptors mediate activity-dependent disinhibition and enhance signal transmission in the dentate gyrus. J Neurophysiol 69:674-91

Showing the most recent 10 out of 15 publications