EMBL/EMBO Joint Conference 2006
Jean-Pierre Changeux, Institute Pasteur, Paris, France
Jean-Pierre G. Changeux is Professor at the Pasteur Institute and at the Collège de France, Paris. He received his Ph.D. in 1964 from Paris University and from 1965-67 completed postdoctoral studies at University of California, Berkeley and Columbia University College of Physicians & Surgeons, New-York. He is member of the National Academy of Sciences, USA and of several foreign academies, and received in particular the Richard Lounsbery prize, the Wolf prize, the Balzan prize, the American Philosophical Society's Karl Spencer Lashley award in neuroscience and the Lewis Thomas Prize for Writing about Science.
Changeux's work has combined meticulous biochemical and functional molecular dissection and theoretical modeling to establish several elementary mechanisms of intracellular and intercellular regulation. As a graduate student, Changeux established the molecular mechanisms underlying bacterial enzyme regulation by selected metabolic ligands and suggested a model for enzymes in which regulatory signals of enzymatic activity were held to act at "allosteric" sites distinct from the sites at which the substrates of the enzyme would bind. His subsequent career strategically and comprehensively validated his pioneering insight, and has lead to important discoveries first with the identification of the acetylcholine receptor and of its allosteric transitions, second into a variety of peripheral central nervous system functions, in part regulated by cholinergic circuits.
Changeux and his team's empirical and theoretical works in the 70's have included the analysis of synapse formation and the extension of a mechanism of "evolution by variation-selection" to the epigenesis of developing neuronal networks by selective stabilization of synapses. In the 90's Changeux and his collaborators have extended their work to nicotinic receptors in the brain, and have demonstrated in mouse models the selective contribution of specific brain nicotinic receptor subunits to nicotine addiction and to executive functions, learning processes, self administration of nicotine, nicotine antinociception and neuroprotection during aging. They were the first to develop the so-called concept of the "sickness of the receptor", which has today achieved fundamental significance. Other research teams have taken up this concept and been able to reveal that some epilepsy is associated with the mutations which alter the allosteric properties of the receptor and that Attention deficit hyperactivity disorders, sudden infant death, and Alzheimer disease are also connected to a deficit of nicotinic receptors.
Last, Changeux and his colleagues have proposed a neural model for access to consciousness, thereby establishing plausible links between the molecular and cognitive levels with the general aim to account for the molecular and neuronal bases of behavior.
Making of the brain: genetic and epigenetic regulations - from molecular biology to consciousness
In the course of human evolution, the complexity of brain connectivity increased dramatically, while that of the genome did not change significantly. Several genetic mechanisms may plausible account for this paradoxical non-linear relationship such as the spatiotemporal and combinatorial action of developmental genes ie homeotic genes, microcephaly genes and/or several others. Alternatively, the state of activity (evoked/spontaneous) of the developing brain, during foetal life and in the newborn, may contribute to the development of brain organisation via "epigenetic" mechanisms such as the selective stabilisation/elimination of developing synapses. Still, such processes are expected to be limited by a "genetic envelope" which may include genes like those responsible for dyslexia, autism or fragile-X mental retardation.
The mechanism of epigenesis by selective stabilisation of synapses was investigated using molecular biology techniques with the nicotinic acetylcholine receptor (nAChR), the best-known neurotransmitter-gated ion channel. Studies with mice deleted for defined subunits of the nAChR revealed a contribution of the spontaneous activity of the retina to the development of the adult visual pathways and maps. Moreover, the analysis of the transcriptional regulation of nAChR genes by electrical activity/neurotrophic factors during motor endplate morphogenesis established causal links between membrane electrical activity and nAChR genes promoters through transcription factors and second messenger pathways.
In the brain, an efficient in vivo method involving the selective re-expression of defined genes by stereotaxic injections of lentiviral vectors is used to investigate the plasticity of adult brain circuits in cognitive learning. The importance of epigenetic regulation of synapse development (and its pathologies) in early learning processes, in cognitive and/or conscious functions & in cultural evolution, is discussed in the case of the development of the newborn infant and its pathologies such as autism, ADHD, sudden infant death disease.
Changeux J.P. The physiology of truth. Harvard University Press: Cambridge, Mass. 2004.
Changeux J.P. & Edelstein S.E. The nicotinic acetylcholine receptors: from molecular biology to cognition. Odile Jacob: Paris 2005.
Maskos U., Molles B.E., Pons S., Besson M., Guiard B.P., Guilloux J.P., Evrard A., Cazala P., Cormier A., Mameli-Engvall M., Dufour N., Cloez-Tayarani I., Bemelmans A.P., Mallet J., Gardier A.M., David V., Faure P., Granon S., Changeux J.P. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature, 436:103-107, 2005.