Mouse Genetic Models for Neuroscience Diseases

We have continued to analyze several strains of knock-in mice generated in our laboratory for several ligand-gated channels, the nicotinic alpha4 receptor and the serotonin 5-HT3 receptor. The nicotinic receptor work is enhanced by a promising strain, Leu9'Ala. This work has generated interesting insights into nicotine addiction, neurodegenerative disease, and epilepsy.

We have developed "proof of concept" transgenic mouse strains that contain GFP tags on their nicotinic receptors and that duplicate mutations underlying human epilepsies. Our work continues on quantitative aspects of transporter function, primarily measured with fluorescence and with knock-in mice. We are using fluorescence to analyze the mobility of GABA transporters. As an interesting side benefit of the GABA transporter knock-in mouse, we have generated and analyzed a knockout mouse for the same molecule.

Some knock-in mice have a hypersensitive subunit; in such mice, responses to nicotine represent selective excitation of receptors containing that subunit.  Other mice have a fluorescent subunit aiding in quantification.

One of our projects involves studying the role of Menthol in tobacco dependence as well as receptor mediated withdrawal.

These strains have encouraged us to ask: What happens in the body when a person smokes a cigarette? What happens after several weeks of smoking? Why do dopaminergic neruons degenerate when people develop Parkinson's disease? And why does smoking appear to lower the probability of a person developing Parkinson's disease? Because there is never a medical justification for the use of tobacco, it is important to understand the mechanism of the apparent neuroprotective effect. To determine whether chronic nicotine induced changes in gene expression contribute to the neuroprotective effects, we use a combination of wet-bench and computational methods to measure the effect of prolonged nicotine exposure on the dopaminergic cell transcriptome in an unbiased manner. nAChRs present themselves as potential candidates in pharmacological intervention for treatment for Parkinson’s disease.