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Neurosteroids: trophic and bevavioral effects

Objectif

To study the mechanisms by which neurosteroids increase the expression of specific myelin proteins.
To test the beneficial effects of neurosteroids in transgenic animal models for hereditary peripheral neuropathies.
To determine whether neurosteroids promote myelination in the central nervous system.
To correlate performance in spatial memory tasks with neurosteroid levels in distinct brain regions.
To explore the mechanisms by which neurosteroid - GABAA receptor interactions influence memory performance in rats and sleep patterns in rodents and humans.
To study the effects of neurosteroids on different recombinant GABAA receptor subtypes and to define the neurosteroid binding site on the mammalian receptor protein.

Neurosteroids are synthesized in the nervous system by glial cells. Recent research, carried out in the laboratories of the participants, has revealed 3 important effects of neurosteroids : they promote the formation of new myelin sheaths, improve spatial memory performance and modify sleep architecture. The mechanisms by which progesterone activates the transcription of specific myelin genes are explored. Transgenic animal models for hereditary peripheral neuropathies allow to test whether neurosteroids can reverse the process of demyelination, characteristic of these diseases. An important question is whether progesterone also promotes myelination by oligodendrocytes in the central nervous system. A particular isoform of the progesterone receptor is expressed in Schwann cells and in oligodendrocytes. The cloning of this new receptor may lead to the design of synthetic progesterone derivatives which would act selectively on the myelinating glial cells. Neurosteroids can influence memory processes. The relationship between their production in specific brain regions and spatial memory performance is studied. Neurosteroids are measured in small brain tissue and microdialysis samples by a new and very sensitive method using gas chromatography - mass fragmentography. The mechanism by which neurosteroids like pregnenolone sulfate and dehydroepiandrosterone sulfate improve memory performance are explored and most likely involve the removal of GABAergic inhibition on cholinergic neurons. Pregnenolone and dehydroepiandrosterone have also a potent influence on sleep architecture in rats and in humans. The changes in electroencephalographic (EEG) spectrum are compatible with an inverse agonistic action of these neurosteroids on the GABAA receptor. To test this hypothesis, the effects of neurosteroids, administered alone or together with GABAergic drugs, are examined. An original molecular biology approach is used to define the neurostroid binding pocket on the mammalian receptor protein, a potential target in the development of new therapeutic agents with selective effects on memory and sleep.

Régime de financement

CSC - Cost-sharing contracts

Coordinateur

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Adresse
80,Avenue De Général Leclerc 80
94276 Le Kremlim Bicetre
France

Participants (4)

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
Adresse
Domaine De Carreire Rue Camille Saint-saëns
33077 Bordeaux
Max-Planck-Gesellschaft zur Förderung der Wissenschaften eV
Allemagne
Adresse
Kraepelinstraße 2-16
80804 München
SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZUERICH
Suisse
Adresse
101,Eth Hoenggerberg, Hpm-i
8093 Zurich
University of Dundee
United Kingdom
Adresse
Ninewells Hospital
DD1 9SY Dundee