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© Uwe Maskos
Tranche d'hippocampe de souris colorée avec deux toxines spécifiques de sous-types de récepteur nicotinique, en rouge (grains), et en vert (corps cellulaires). L'hippocampe est la zone du cerveau qui gère la mémoire spatiale.
Scientific Fields
Diseases
Organisms
Applications
Technique

About

The nicotinic receptor is at the basis of nicotine addiction, which presents a serious social and public health problem. It is the single most important preventable factor of mortality and morbidity worldwide. More than 100 million people are expected to die this century from the consequences of smoking, and also second hand smoke.
But it is also a major player in a number of other pathologies, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, multiple sclerosis and ALS. Hence, the identification of the molecular mechanisms and circuits involved urgently requires the development of novel tools allowing genetic and molecular manipulation in vivo, in experimental animals, and human induced pluripotent stem cells (hiPSC).

Over the last years, we have based most of our work on robust Genome-wide Association Studies (GWAS) linking human polymorphisms in genes coding for the nicotinic acetylcholine receptor (nAChR) to smoking. We have focused on a coding Single Nucleotide Polymorphism (SNP) in the CHRNA5 gene, coding for the alpha5 nAChR subunit, and dissected its role in reinforcement, consumption levels, and relapse. Analysing the role of a second gene linked through GWAS, CHRNB4, coding for the beta4 nAChR, we were able to identify a new circuit determining nicotine intake, and implicating the medial habenula-interpeduncular pathway. These findings have led to an approach of “precision medicine”.

A second pathology addressed is schizophrenia, and its relationship with heavy smoking. There also, large-scale GWAS identified the same human polymorphisms, a haplotype on chromosome 15q. Using advanced two-photon imaging in the wake behaving mouse, we were able to identify a network of cortical interneurons expressing nAChRs, and a key role for the alpha5 SNP in reduced cortical activity reminiscent of “hypofrontality” in human patients. This altered activity is restored by the application of chronic nicotine, lending support to the “self-medication” hypothesis, i.e. psychiatric patients smoke to alleviate symptoms of the disease.

We have also been able to elucidate a role for nAChRs in Alzheimer’s disease (AD), where a “protective” role of nicotine, or even smoking, is debated. In animal models, AD-like pathology is reduced in the absence of the high affinity beta2 nAChR subunit. This is the subunit responsible for the high affinity binding of nicotine, and is “desensitised” in the brains of smokers. This has led to a patent, and a novel strategy to prevent the progression of the disease.

Finally, GWAS and meta-analysis have also revealed a role for the same alpha5 nAChR SNP in lung cancer and Chronic Obstructive Pulmonary Disease (COPD), one of the main unresolved diseases worldwide. This work, implicating “neuronal” nAChRs in non-neuronal, bronchial epithelial stem cells, is supported by major French gouvernmental programmes (Plan Cancer).

Highlights for future research include:

⎫ Comprehensive mechanistic analysis in several transgenic rat models

⎫ A novel system for the study of human iPSC derived neurons in vivo

⎫ An approach for personalised medicine targeting human nAChR polymorphisms

⎫ A novel approach to target Alzheimer’s disease

Biomedical research on the role of the nicotinic receptor in lung cancer and COPD

⎫ The nicotinic receptor and its relationship with the microbiome and immune system

Members

Former Members

2000
2000
Name
Position
2015
2020
Lauriane Harrington
PhD Student
2015
2020
Sylvia Lombardo
PhD Student
2015
2020
Stefania Tolu
PhD Student
2015
2020
Stéphane Blanchard
Technician
2015
2020
Cristina Deflorio
Post-doc
2015
2020
Delphine Bohl
Head of Facility
2015
2020
Elena Simonazzi
Graduate Student
2015
2020
Maria-Carla Carisì
Graduate Student
2015
2020
Giorgia Conte
Graduate Student
2015
2020
Valentina Serpieri
Graduate Student
2015
2020
Tiago David
Graduate Student
2015
2020
Micol Alberti
Graduate Student
2015
2020
Marianne Husson
Post-doc
2015
2020
Amandine Anastasio
Research Engineer
2015
2020
Rosa D’Alessio
Research Engineer
2015
2020
Luana Pitasi
Graduate Student
2015
2020
Dana Kroitorou
Graduate Student
2015
2020
Léa Vanni
Graduate Student
2015
2020
Anais Rahimian
Graduate Student
2015
2020
Christiane Bils
Graduate Student
2015
2020
Caroline Correia
Graduate Student
2015
2020
Cynthia Rais
Graduate Student
2015
2020
Rodolphe Blanco
Graduate Student
2015
2020
Sylvana Tahraoui
Technician
2015
2020
Ferenc Balázs FARKAS
Undergraduate Student
2015
2020
Alina Lakosa
Graduate Student
2015
2020
Daniela Santos
Graduate Student
2015
2020
Michael Maar
Graduate Student
2015
2020
Flavio Tomasi
Graduate Student
2015
2020
Vinita Jagannath
Post-doc
2015
2020
Noor Mimoun
Undergraduate Student
2015
2020
Benoît Forget
Post-doc
2012
2019
Fani Koukouli
PhD student, Post-doc
2019
2020
Vithurshana Pakirathan
Undergraduate Student
2019
2020
Marta Balkota
Graduate Student
2019
2020
Candice Cannone
Undergraduate Student
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Pictures & Media

These videos show scans through transplants of human iPSC derived neurons. They are from our recent paper in Developmental Biology: https://pubmed.ncbi.nlm.nih.gov/31982375/

Contact

Address: Institut Pasteur, Bâtiment Fernbach, 25 rue du Dr. Roux, 75724 Paris cedex 15, France e-mail: uwe.maskos@pasteur.fr Phone: (33) 1 45 68 88 06