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The Journal of Neuroscience, May 1, 2003, 23(9):3837

Conditional Expression in Corticothalamic Efferents Reveals a Developmental Role for Nicotinic Acetylcholine Receptors in Modulation of Passive Avoidance Behavior

Sarah L. King¹, Michael J. Marks², Sharon R. Grady², Barbara J. Caldarone¹, Andrei O. Koren³, Alexey G. Mukhin³, Allan C. Collins², and Marina R. Picciotto¹

¹ Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, ² Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309, and ³ Brain Imaging Center, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland 21224

Prenatal nicotine exposure has been linked to attention deficit hyperactivity disorder and cognitive impairment, but the sites of action for these effects of nicotine are still under investigation. High-affinity nicotinic acetylcholine receptors (nAChRs) contain the 2 subunit and modulate passive avoidance (PA) learning in mice. Using an inducible, tetracycline-regulated transgenic system, we generated lines of mice with expression of high-affinity nicotinic receptors restored in specific neuronal populations. One line of mice shows functional 2 subunit-containing nAChRs localized exclusively in corticothalamic efferents. Functional, presynaptic nAChRs are present in the thalamus of these mice as detected by nicotine-elicited rubidium efflux assays from synaptosomes. Knock-out mice lacking high-affinity nAChRs show elevated baseline PA learning, whereas normal baseline PA behavior is restored in mice with corticothalamic expression of these nAChRs. In contrast, nicotine can enhance PA learning in adult wild-type animals but not in corticothalamic-expressing transgenic mice. When these transgenic mice are treated with doxycycline in adulthood to switch off nAChR expression, baseline PA is maintained even after transgene expression is abolished. These data suggest that high-affinity nAChRs expressed on corticothalamic neurons during development are critical for baseline PA performance and provide a potential neuroanatomical substrate for changes induced by prenatal nicotine exposure leading to long-term behavioral and cognitive deficits.

Key words: nicotine; learning; transgenic mice; nicotinic acetylcholine receptors; brain; prenatal

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2393837-07$05.00/0

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