Human Polymorphisms in Nicotinic Receptor Genes---Modeling their role in nicotine dependence and co-morbidities using transgenic rats and mice – SNP-NIC

There is very robust human genetic evidence confirmed by meta-analysis of Genome-Wide Association Studies (GWAS)
that human single nucleotide polymorphisms (SNPs) in the CHRNA5/CHRNA3/CHRNB4 cluster on chromosome 15q are
linked to smoking risk, the age of initiation, the number of cigarettes smoked, and the response to smoking cessation
treatment. There is additional evidence that smoking is highly prevalent in several classes of psychiatric disease,
especially schizophrenia. In the recent first-ever robust GWAS on schizophrenia, the same locus was identified very
prominently as being linked to schizophrenia.
We have generated transgenic mice and rats expressing a frequent coding polymorphism in the CHRNA5 gene,
rs16969968, coding for the alpha5 subunit of the nicotinic acetylcholine receptor (nAChR), changing an aspartate to
asparagine at position 398 (D398N). This SNP has an allele frequency of 35% in Caucasians.
Here, we propose to dissect the underlying mechanisms that lead to the initiation of nicotine consumption, the level of
consumption measured in transgenic rats undergoing self-administration paradigms, and the mechanism of relapse
specifically observed in transgenic rats expressing the human D398N polymorphism, a5SNP.
Furthermore, we have set up dynamic two-photon imaging in the cortex of awake mice, and started to analyse mice with
the expression of a5SNP in the cortex. These mice exhibit "hypofrontality" similar to imaging studies carried in human
carriers of the a5SNP. We will dissect this change in cortical activity, and identify the factors why chronic nicotine
application normalises it. This effect can be linked to the smoking incidence in psychiatric patients, where nicotine is
considered as a form of "self-medication".
Next, we complete this analysis with advanced behavioural dissection, in vivo electrophysiology and EEG recordings of a
novel decision making task published very recently [1].
We finish by giving an outlook of how these animal studies can be extended using RNAseq approaches and the
translation into the targeting of novel pathways for smoking cessation and normalisation of altered cholinergic signaling in
mental disease.