Project: A functional dissection of human nicotinic receptor polymorphisms linked to addiction and schizophrenia

Acronym iPS&BRAIN
Duration 30/04/2019 - 30/04/2020
Project Topic In the proposed work we will study the function of human polymorphisms in nicotinic acetylcholine receptor (nAChR) genes in nicotine addiction and schizophrenia. These disorders are major issues for public health. Our project is based on robust Genome-wide Association Studies (GWAS), confirmed by meta-analysis, that link coding and non-coding Single Nucleotide Polymorphisms (SNPs) in humans to these major pathologies of the nervous system. We are proposing a bottom-up approach to study human polymorphisms in the CHRNA5, CHRNA7 and CHRFAM7A genes, coding for the nAChR alpha5, alpha7 and the partially duplicated alpha7 subunit, termed dupa7, a human-specific gene. Their role, function and involvement in synaptic pathology will be studied in differentiated human induced pluripotent stem cell (hiPSC) derived neurons in vitro, in vivo after transplantation into the mouse brain, and in slices obtained from human cortex. These polymorphisms will be further modeled after introduction into transgenic mice and also rats. These lines exist already, and will be used for functional two-photon imaging in prefrontral cortex, and in behavioural assays. The results of the proposed work will contribute to further our understanding of the underlying synaptic alterations, and allow to create novel medication, acting on the genetically altered receptors, to progress towards personalised treatments for the carriers of the SNPs.
Network NEURON Cofund
Call Call for Proposals for Research Projects on "Synaptic Dysfunction in Disorders of the Central Nervous System"

Project partner

Number Name Role Country
1 Institut Pasteur Coordinator France
2 VU Amsterdam Partner Netherlands
3 Medical University Vienna MUW Partner Austria