Jean-Pierre Changeux,
Pasteur Institute, Paris, France
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. |
