Studies with Nicotinic Null Mutant Mice

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Neuronal nicotinic cholinergic receptors are expressed throughout the brain, in the spinal cord, and in the autonomic ganglia. Eleven neuronal nAChR subunit genes were cloned and sequenced in the 1980's. Some of these subunits closely resemble the a1 subunit that is included in the nAChR that is expressed at the neuromuscular junction (the so-called peripheral-type receptor). These 01-like subunits are called: a2, a3...a10 and, with the exception of a5, provide the binding site for nicotine and other nicotinic agonists. The three remaining subunits, 02-04, are referred to as structural subunits. Enormous progress has been made towards understanding the structure and function of neuronal nAChRs using expression systems (cell lines, Xenopus laevis oocytes). For example, expression system studies have shown that subunit composition has profound effects on biophysical and pharmacological properties. The value of expression system studies has been limited, somewhat, because some of the more interesting subunits (e.g. a6,03) are not easily expressed in artificial systems. These, and other concerns, have prompted researchers to develop gene knockout (null mutant) mice for virtually every one of the known nAChR subunits. Transgenic mice have also been developed that express several gain of function mutations, or mutations that are associated with human diseases. These transgenic mice are being used to address questions such as: 1) What are the subunit compositions of naturally-occurring (i.e. native) nAChRs? 2) Where are these native receptors expressed? 3) What role do they play in modulating brain function (behavior?), and 4) What function do these receptors play in modulating addiction to nicotine, alcohol and other drugs? We have the world's most complete collection of nAChR mutant mice that are being used in several funded research projects that are centered at the University of Colorado. During the last 4 years we have built our colony from five mutant strains to 18 and have established a system where we have sent mice and/or breeding pairs to other researchers in the US and, more recently around the world (3 continents, to date). This application requests funds to support the continued maintenance and distribution of these mouse stocks.