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  • Phone : +33 1 49 59 18 35
  • Location : Le Kremlin-Bicêtre, France
Last update 2011-08-30 15:10:29.327

Dominique Chesnoy-Marchais Chloride channels, glycine receptors, neurosteroids, synaptic transmission, PhD Neurobiology

Course and current status

Studies and diploma
1974-1977: Engineer, Ecole Polytechnique, Paris, France (X 1974)
1977-1978 : Training in Neurobiology
- 1977 : Diploma in Molecular Pharmacology, Option Neurobiology (DEA, Univ Paris 6)
- Research in Lab. de Neurobiologie, Ecole Normale Supérieure (ENS), Paris, with Dr. J.M. Dubois
- Research in Lab. de Physiologie Cellulaire, Collège de France, Paris, with Dr. J. Bockaert
1979: Thesis  (Univ Paris 6) with Dr. A. Marty, in Lab. de Neurobiologie, ENS
1979-1983 : « Doctorat ès Sciences » (Univ Paris 6) under direction of Dr. P. Ascher, at ENS

Main position 
Researcher CNRS (Centre National de la Recherche Scientifique) since october 1979
1979-2001 : Laboratoire de Neurobiologie, ENS, Paris (Director : Dr. P. Ascher).
Electrophysiological studies of various types of ionic channels and responses to neurotransmitters and hormones, on invertebrate neurons, rat osteoblasts, rat spinal cord neurons, and a few other cell types, using intracellular voltage-clamp and patch-clamp techniques. Special interest for Ca2+ and Cl- channels, in particular for Cl- responses to a main inhibitory neurotransmitter, glycine
2003 : Creation of a patch-clamp laboratory in U488, “Steroïdes et système nerveux” (now U788) at INSERM-Univ Paris 11, in Le Kremlin-Bicêtre (Director : Dr. M. Schumacher)
Since 2003 : Patch-clamp study of inhibitory glycinergic synaptic responses and modulation by neurosteroids of glycine and GABA Cl- responses in identified motoneurons from rat brain stem slices

Other activities
Consultant for Rhône-Poulenc Pharmuka (1986-87)
Author & Editor of a book, “Physiologie du Neurone” (1998), translated in Japanese
Reviewer of papers in neuroscience, physiology, neuropharmacology, endocrinology
Expert in thesis committee, for grant proposals and, in 2003-2004, for « Ministère délégué à la Recherche, Mission Scientifique Technique et Pédagogique, Département Scientifique Pédagogique et Technique DSPT5 »
Teaching mainly in University Paris 6 (up to 2001) and in University Paris11 (since 2003)

Scientific summary

1980-1983 : Voltage-clamp intracellular recordings of K+ and Cl- channels in Aplysia neurons
- Detection of interactions between K+ responses to various neurotransmitters
- Detection of a novel type of voltage-sensitive Cl- current, activated by hyperpolarisation in an intracellular Cl- -dependent manner
Similar channels were cloned later by Jentsch’s group (1990-1992). It is now clear that in mice hippocampal pyramidal neurons, the ClC-2 channel is vital for allowing efflux of accumulated internal Cl- (Nature Neurosci 2010).

1983-1986 : Single-channel patch-clamp recordings in Aplysia neurons
- Hyperpolarisation-activated Cl- channels
- Channels permeable to both Ca2+ and Mg2+, activated by depolarisation, with kinetic properties strikingly dependent on the nature of the main external divalent cation
- Non-selective ionic channels, permeable to both anions and cations

1986-1993 : Patch-clamp study of rat osteoblasts’ electrical properties
- Detection of voltage-gated currents able to trigger action potentials in these bone cells
Na+ current, K+ currrents, Ca2+ currents, activated by depolarisation
- Cl- currents and osmotic-sensitivity
Cl- current activated by external hypo-osmolarity, distinct from the hyperpolarisation-activated Cl- current
- Hormonal and intracellular modulations
Effects of parathyroid hormone, vitamin D3, arachidonic acid and cyclic nucleotides

1993-1995 : Glutamate/NMDA cationic responses in rat cultured spinal neurons
Interactions between NMDA receptors and serotonin (5-HT) receptors’ ligands

1995-2001: Chloride  responses to exogenous glycine in cultured spinal neurons
- Detection of a potentiation of Cl- responses to glycine by some 5-HT3 antagonists, including tropisetron (ICS-205,930). This new pharmacological property has been confirmed in purified motoneurons and in Xenopus oocytes expressing homomeric or heteromeric recombinant glycine receptors. A major role of the beta subunit has been revealed. These results, confirmed by other groups, have encouraged the research of new therapeutic agents, expected to show antinociceptive and antispasmodic properties : potent and selective potentiators of inhibitory glycine receptors.
- Interactions between glycine receptors and some Ca2+ channel antagonists
- Detection of a potentiation of Cl- responses to glycine by tamoxifen, prototype of the “selective oestrogen receptor modulators” family, widely used for breast cancer treatment.

 2003-2008 : Modulation of synaptic glycinergic responses by tamoxifen and oestradiol in hypoglossal motoneurons of rat brainstem slices
- Demonstration that tamoxifen increases both the amplitude and the frequency of glycinergic spontaneous miniature synaptic currents
This confirms the increase in glycine-sensitivity of postsynaptic glycine receptors and reveals a new presynaptic effect of this ligand of oestrogen receptors : an increase of the tonic release of a major inhibitory neurotransmitter by presynaptic terminals.
Demonstration that oestradiol increases the spontaneous synaptic release of glycine
This result was quite new and surprising. This modulation is clearly inhibitory, since glycine markedly lowers the excitability of the motoneurons studied, whereas previously, oestradiol was mainly known for an excitatory modulation, the facilitation of glutamatergic neurotransmission. Furthermore, this was the first evidence for a presynaptic effect of oestradiol on neurotransmitter release. Interestingly, very recently, the effect of oestradiol on glutamatergic transmission also appeared to involve a presynaptic increase in transmitter release. The glycine release induced by oestradiol is interesting in relationship with its neuroprotective effects. Under pathological situations, in neurons receiving a strong glycinergic inhibitory synaptic input, an increase in spontaneous glycine release should prevent glutamatergic over-excitation and thus contribute to neuroprotection.

2008-2010 : Modulation of synaptic glycinergic responses by progesterone and some of its metabolites
Progesterone is now under clinical trial for its neuroprotective properties. Some of its 5alpha-reduced metabolites are well-known to potentiate GABAA Cl- responses. However, the effects of progesterone on neurotransmission have not been fully explored. I showed that progesterone can increase the miniature synaptic release of glycine on motoneurons, and that this effect is indirect. It results from the metabolism of the hormone into 5alpha-reduced derivatives, in particular allopregnanolone, which mimics the effect of progesterone. It was also shown that, at the presynaptic level, Cl- responses to GABA and glycine are depolarising. Potentiation of a depolarising presynaptic activity by some progesterone metabolites can explain the observed increase in glycine release. Since glycine strongly inhibits the postsynaptic neurons, the glycine release induced by the active progesterone metabolites can contribute to their protective effect against excitotoxicity.

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