Jim Boulter Laboratory:
[Publications]
Research Interests:
The long-term research objective of our laboratory is to use a molecular genetic approach to understand the role of nicotinic acetylcholine receptors (nAChRs) in vertebrate central and peripheral nervous system function. Although considerable molecular data regarding the structure and function of the ten known nAChR subunit genes is available, far less is known about neural circuitry or roles subserved by the individual receptors assembled from the various subunits. Moreover, little is known about the physiological consequences of mutations within these genes, the precise roles of receptor subtypes in the normal ontogeny and modulation of central nervous system synapses, or in the establishment of nicotine-induced dependence, tolerance, and withdrawal among habitual tobacco users.
As a first step towards addressing some of these issues, our lab is conducting experiments which use homologous recombination in mice to introduce null or altered-function mutations in selected nAChR subunit genes. The rationale for such studies rests on the assumption that deficits or alterations in targeted genes can, upon analysis of subject animals, reveal or clarify the function of the mutated gene.
Ongoing projects include construction of a transgenic mouse containing a deletion of the nAChR alpha 6 subunit gene. Since alpha 6 is actively transcribed in catecholaminergic nuclei (ventral tegmental area, substantia nigra, and locus coeruleus), it is anticipated that null mutants will help to define central cholinergic circuits which modulate locomotion. Likewise, an alpha 6 null mutation is anticipated to have profound effects on behaviors which originate in the mesolimbic dopamine system and are relevant to the reinforcing properties of nicotine, or to the basic motivational processes which underlie learning and cognitive behavior.
A second genetically engineered mouse will harbor a specific mutation (Ser248Phe) in the nAChR alpha 4 subunit gene. In vitro this mutation potentiates onset and slows recovery from receptor desensitization, while in vivo this mutation is responsible for a human disorder known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The purpose of this set of experiments is to provide an animal model to analyze the molecular pathology of partial epilepsy, and to offer a paradigm for the development and evaluation of cholinergic therapeutic strategies.
Finally, we are beginning a new project in the lab to determine the possible role of central and peripheral nAChR in the perception of pain. Recent experiments from a number of laboratories have demonstrated that synthetic derivatives of epibatidine (a high affinity, naturally occurring, nicotinic cholinergic agonist) are potent analgesics which show considerable promise for the treatment of chronic, neurodegenerative and inflammatory pain. To determine which nAChRs are involved in peripheral nociception we are examining the repertoire of nAChR genes expressed in spinal cord and dorsal root ganglion neurons (primary sensory afferents) using a combination of in situ hybridization, immunocytochemistry, and reverse-transcription PCR.
Laboratory Phone: (310)206-9080
Laboratory Staff:
Alwin Klaassen |
Janet Byun |
|
Jim Boulter, Ph.D.
Associate Professor
Email:
Phone:
(310)206-6665