Neuroscience Department Activity Report

The Department of Neuroscience is composed of about a hundred staff members, including 70 scientists. Its composition, as of January 1st, 2008, comprises four Units and three G5 groups, including a new G5 group headed by Pierre Jean CORRINGER that was created in January 2008.

G5 “Human Genetics and Cognitive Functions” headed by Thomas BOURGERON

This group explores the genetic contributions to social communication in humans by studying the genetic susceptibility to psychiatric conditions such as autism spectrum disorders. The group has previously described two genes involved in autism and identified two additional genes (SHANK3 and NRXN1) in 2007. All these genes encode synaptic proteins. The group also recently described genetic alterations of the melatonin synthesis pathway (ASMT), which are associated to autism.

G5 “Nematode Genetics” headed by Bernard LAKOWSKI

This group uses Caenorhabditis elegansto address the biological role of homologues of certain human disease genes. The work includes the identification and the study of several genes that bypass the need for the sel-12presenilin gene. They encode proteins similar to components of the human REST-CoREST complex that regulates neuronal gene expression and plays a role in neuronal stem cell fate.

U “Retroviruses and Gene Transfer” (INSERM U622) headed by Jean-Michel HEARD

The unit focuses on gene therapy for central nervous system disorders. A trial based on the direct injection of AAV vectors in the brain for the treatment of a paediatric neurodegeneration associated with lysosomal storage diseases is being prepared. Recent work on these diseases demonstrate the respective roles of inflammation and cell autonomous developmental defects in the loss of neuronal plasticity. Others work performed in 2007 showed that the directed differentiation of neural stem cells into motor neurons provides new approaches to investigating pathogenesis and conceiving treatments in motor neuron degenerative disorders.

UP “Integrative Neurobiology of Cholinergic Systems” headed by Uwe MASKOS

Using original animal models, the group showed that the immediate effects of nicotine on behaviour and electrophysiology are mediated by the B2* nicotinic receptors, whereas long-term effects are mediated through the A7* receptors, providing new concepts with pharmacological relevance. Experimental evidence for the neuroprotective effects of the B2* receptors were also provided, supporting epidemiological data previously obtained in patients with Parkinson or Alzheimer diseases.

U “Perception and Memory” (CNRS URA 2182) headed by Pierre-Marie LLEDO

This laboratory is addressing the processing of sensory information in the olfactory bulb and is taking advantage of the continuous renewal of inter-neurons in this organ to investigate processes underlying adult neurogenesis. The aim is to answer fundamental issues and to develop new therapeutic strategies.

U “Genetics and Physiology of Hearing” (INSERM UMRS 587) headed by Christine PETIT

The laboratory of Genetics of Sensory Deficits has just been renamed “Genetics and Physiology of Hearing”. It aims at understanding the molecular and cellular bases of sound processing in the cochlea and the primary auditory neurons by making full use of causative genes for hearing impairment in humans. It has identified more than 20 of these genes and clarified their associated defective mechanisms. It has recently revealed a novel pathogenic process related to the absence of connexin 30. It consists in the disruption of the endothelial barrier of the capillaries supplying the stria vascularis. The resulting electric shunt prevents the generation of the endocochlear potential essential to the auditory mechanotransduction.

Events

In 2007, several members of the Department have organized European and international meetings.

Our Department Seminar, held on December 6-7th in Marly-le-Roi, has been a key event in the life of the department. Owing to the joint efforts and talent of Uwe Maskos and the scientists who worked with him to help, it was a real scientific success. It also provided an opportunity to interact with group leaders and chairmen from other departments of the Institut Pasteur in a friendly atmosphere.

Perspectives

Our department’s interests are mainly focuses on the neural basis of sensory perception, behavior and cognition, as well as in their related disorders with the objective of developing preventive and therapeutic approaches.

We aim at elucidating the 3D structure of ionic channels and/or their associated molecules as well as to decipher in real-time the interactions of these proteins in a single neuron or sensory cell in order to correlate these interactions with the electrical activity. Our purpose also is to understand how sensory information is processed from the sensory cell up to the cortex. We consider this issue in the broader perspective of neuronal circuits and with the ultimate goal of enlightening the way animals select appropriate action on the basis of sensory information, experience and motivation. As regards the nervous system dysfunctions, our objective is to clarify the molecular and cellular bases of CNS neurodegenerative disorders and social communication disorders with particular interest in autism, addiction to nicotine, and hearing impairment. We view this knowledge as the corner stone for the development of therapies.

Major publications

Besson M, Granon S, Mameli-Engvall M, Cloëz-Tayarani I, Maubourguet N, Cormier A, Cazala P, David V, Changeux JP, Faure P (2007) Long-term effects of chronic nicotine exposure onbrain nicotinic receptors.Proc Natl Acad Sci USA104, 8155-8160.

Bocquet N, Prado de Carvalho L, Cartaud J, Neyton J, Le Poupon C, Taly A, Grutter T, Changeux JP,Corringer PJ. (2007) A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family.Nature445, 116-119.

Cohen-Salmon M, Regnault B, Cayet N, Caille D, Demuth K, Hardelin J-P, Janel N, Meda P & Petit C (2007) Connexin30 deficiency causes intrastrial fluid-blood barrier disruption within the cochlear stria vascularis. Proc Natl Acad Sci USA104, 6229-6234.

Durand C, Betancur C, Boeckers TM, Bockmann J, ChasteP, FauchereauF, NygrenG, Rastam M, Gillberg IC, Anckarsäter H, SponheimE, Goubran-BotrosH, DelormeR, ChabaneN, Mouren-SimeoniMC,de MasP, BiethE, RogéB, HéronD, BurglenL, GillbergC, LeboyerM, Bourgeron T (2007) Mutations of the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet39, 25-7.

Lagier S, Panzanelli P, Russo R, Sassoè-Pognetto M, Fritschy JM, Lledo P-M. (2007) GABAergic inhibition at dendro-dendritic synapses tunes gamma oscillations in the olfactory bulb.Proc Natl Acad Sci USA104, 7259-64.

Michalski N, Michel V, Bahloul A, Lefèvre G, Barral J, Yagi H, Chardenoux S, Weil D, Martin P, Hardelin J-P, Sato M & Petit C (2007) Molecular characterization of the ankle link complex in cochlear hair cells and its role in the hair bundle functioning. 27, 6478-6488.

Prix et nominations reçus par les membres du département

Human Genetics and Cognitive Functions

Thomas BOURGERON: Prix Lacassagne Fondation Hugot du Collège de France.

Prix des victoires de la médecine 2007 (with Marion Leboyer).

Christelle DURAND : Médaille de l’Académie des Sciences pour "Les grandes avancées en biologie française 2006-2007 présentées par leurs auteurs".

Integrative Neurobiology of Cholinergic Systems

Philippe FAURE: Prix de la Fondation Gilbert Lagrue

Perception and Memory

Pierre-Marie LLEDO: Prix Jaffe de l’Académie des Sciences

Genetics and Physiology of Hearing

Christine PETIT: Grand Prix INSERM de la Recherche Biomédicale