Biomedical subjects

Francois Tronche

Publications and source records attributed to Francois Tronche.

4 recordsLinked to original sources

PubMed2006

Maturation and maintenance of cholinergic medial septum neurons require glucocorticoid receptor signaling.

Glucocorticoids have been shown to influence trophic processes in the nervous system. In particular, they seem to be important for the development of cholinergic neurons in various brain regions. Here, we applied a genetic approach to investigate the role of the glucocorticoid receptor (GR) on the maturation and maintenance of cholinergic medial septal neurons between P15 and one year of age by using a mouse model carrying a CNS-specific conditional inactivation of the GR gene (GRNesCre). The number of choline acetyltransferase and p75NTR immuno-positive neurons in the medial septum (MS) was analyzed by stereology in controls versus mutants. In addition, cholinergic fiber density, acetylcholine release and cholinergic key enzyme activity of these neurons were determined in the hippocampus. We found that in GRNesCre animals the number of medial septal cholinergic neurons was significantly reduced during development. In addition, cholinergic cell number further decreased with aging in these mutants. The functional GR gene is therefore required for the proper maturation and maintenance of medial septal cholinergic neurons. However, the loss of cholinergic neurons in the medial septum is not accompanied by a loss of functional cholinergic parameters of these neurons in their target region, the hippocampus. This pinpoints to plasticity of the septo-hippocampal system, that seems to compensate for the septal cell loss by sprouting of the remaining neurons.

Acetylcholine↗

PubMed2005

Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone.

The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways.

Adrenal Cortex Hormones↗

PubMed2003

Using conditional mutagenesis to study the brain.

Conditional genetic modifications are used to determine how individual molecules contribute to the function of defined neuronal circuits in the mouse brain. Among various techniques for these genetic modifications, the tetracycline transactivator and the Cre-loxP systems have proved to be most successful in recent years. Here we describe the basic principles, recent developments, and potential applications of these methodologies. We discuss their impact on the study of general brain function and their use for modeling different brain disorders.

Animals↗

PubMed2003

Lack of gp130 expression in hepatocytes promotes liver injury.

BACKGROUND & AIMS: Interleukin 6 (IL-6) contributes via its signal transducer gp130 to the acute phase response (APR) in hepatocytes. Recent studies indicated that IL-6 is involved in the regulation of different pathophysiologic conditions of the liver. To define the IL-6-dependent intracellular pathways more specifically, we generated a hepatocyte-specific gp130 knockout mouse. METHODS: Hepatocyte-specific gp130-deficient mice were generated using the Cre-loxP system. Expression of the Cre recombinase was under the control of a hepatocyte-specific control element. Adult mice were challenged with IL-6, oncostatin M (OSM), and LPS. RESULTS: Cre expression started at day 10.5 postconception, and a complete deletion of gp130 in hepatocytes was found at day 14 during liver development. The adult liver of these mice showed no abnormalities; however, after IL-6 and OSM stimulation, gp130-dependent pathways (STAT3, APR gene expression) were completely blocked in the liver of these animals. Additionally, challenging hepatocyte-specific gp130 knockout animals with lipopolysaccharides (LPS) lead to an onset of acute liver injury with an increase of hepatocyte apoptosis associated with elevated tumor necrosis factor alpha (TNF-alpha) serum levels and reduced nuclear factor kappaB (NF-kappaB) activation in hepatocytes. CONCLUSIONS: Our findings demonstrate that gp130 is of minor relevance for embryonal development of hepatocytes. However, the molecule has an essential role in controlling acute phase gene expression and provides hepatocellular protection after LPS challenge.

Animals↗