Unit: Receptors and Cognition - CNRS URA 2182

Director: CHANGEUX Jean-Pierre

During 2004, the unit has identified the protein microdomain that controls the up-regulation of the nicotinic receptor elicited by chronic exposure to nicotine; identified the role of the C-terminal portion of the receptor in maturation and targeting; analyzed the role of the 14.3.3 protein gamma in the transcriptional regulation of synaptic proteins; demonstrated the modulation of the nicotinic receptors in white blood cells of the smoker and of mice treated with nicotine; identified the role of the high affinity nicotinic receptors in the regulation of sleep in the mice; distinguished the effects of nicotine on the inhibitory and excitatory neurons in the spinal cord ; demonstrated the regulation of the number of neurons in the new-born mice olfactory bulb by the nicotinic receptor and proposed a new model of neuronal network that learns delayed response tasks.

The activity of the " Receptors and Cognition CNRS 2182 " Unit is centered on the study of the nicotinic acetylcholine receptor, an " allosteric " membrane protein involved in the transduction of chemical neurotransmittor signals into electrical responses at the level of the postsynaptic membrane of the neuromuscular junction and of the central nicotinic synapses.

The four main objectives are :

1) identification, at the amino acid level, of the elementary structures engaged in the recognition of nicotinic ligands, in ionic selectivity and transport and in their diverse modes of " allosteric " coupling (activation, desensitization) and in " up regulation " to chronic exposure to nicotine.

2) the regulatory mechanisms of gene expression involved in the focal distribution of nicotinic receptors in muscle endplate postsynaptic membrane (in the course of development and in the adult) and in the differential distribution of nicotinic receptors in the brain.

3) the neural processes taking place in the dendritic vs. axonal compartments of central neurons and involved in learning and reward mechanisms associated with nicotine addiction and various brain pathologies

4) the demonstration of causal relationships between the molecular properties of neuronal nicotinic receptors and their distribution with brain physiology and behavior.

5) the theoretical modeling of formal neuronal networks establishing bottom up and top-down links between the molecular and cognitive level and its plausible applications to human behavior and pathologies.

The methods used to attain the first objective include crystallization of the purified protein (or specific fragments) and analysis of the three-dimensional fonctional organization by site-directed mutagenesis, stopped-flow with fluorescent ligands in wild type and mutant brain nicotinic receptors. To attain objectives 2 and 3, the most recent advances in recombinant DNA technologies, cloning and sequencing of cDNAs in situ hybridization, promoter analyses, in vivo and in vitro transfection experiments, conditional homologous recombination in vivo and stereotaxic injection of lentiviral vectors are being exploited, along with cell biology methods such as confocal microscopy, cell imaging and small animal fMRI.

Ongoing applications of the current work to medicine include ; (1) the pharmacology of peripheral and central nicotinic synapses in relation with the effect of nicotine in addiction, cognitive enhancement, anagesia, anesthesia, and neuroprotection.

(2) the pathology of skeletal muscle in its innervated conditions and after denervation, the pathology of myasthenia gravis and myesthenic syndromes.

(3) brain defects resulting from (or associated with) alterations of nicotinic receptors such as frontal lobe, epilepsy, Alzheimer's and Parkinson's disease, analgesia, aging and nicotine addiction.

Among the original works published in 2004, one may mention :

1) The identification of an extracellular microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine. (Salette et al 2004).

2) The demonstration of the Critical role of the C-terminal segment in the maturation and export to the cell surface of the homopentameric alpha7-5HT receptor. (Pons et al 2004).

3) The demonstration that 14-3-3 protein gamma associates with muscle specific kinase and regulates synaptic gene transcription at vertebrate neuromuscular synapse (Strochlic et al 2004)

4) The evidence that long-term exposure to nicotine modulates the level and activity of acetylcholine receptors in white blood cells of smokers and model mice (Cormie et al 2004).

5) The reduction of withdrawal signs after chronic nicotine exposure of alpha-calcitonin gene-related peptide knock-out mice (Salmon et al 2004).

6 The demonstration that beta2-containing nicotinic receptors contribute to the organization of sleep and regulate putative micro-arousals in mice (Lena et al 2004).

7) The evidence that persistent decrease in synaptic efficacy induced by nicotine at Schaffer collateral-CA1 synapses in the immature rat hippocampus (Maggi et al 2004).

8) The demonstration that nicotine differentially activates inhibitory and excitatory neurons in the dorsal spinal cord (Cordero-Erausquin et al 2004)

9) The observation that nicotinic receptors regulate the survival of newborn neurons in the adult olfactory bulb (Mechawar et al 2004).

10) The elaboration of a Neural Network Model that acquires performs of Delayed-response Tasks : (Gisiger et al 2004).

Title : The microdomain of brain nicotinic receptors that govern up-regulation by chronic nicotine

Legend : Model of the extracellular domain of the α3β2 nicotinic receptor with an acetylcholine molecule in its specific binding site (represented in yellow) and the protein microdomain of 16 amino-acids (represented in green and red) that governs both the maturation and the up-regulation by chronic nicotine of the brain heteromeric nicotinc receptors.

Keywords: nicotinic acetylcholine receptors , allosteric proteins , learning , knockout mice , nicotine addiction

Activity Reports 2004 - Institut Pasteur

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