Mouse Strain-Specific Nicotinic Acetylcholine Receptor Expression by Inhibitory Interneurons and Astrocytes in the Dorsal Hippocampus LORISE C. GAHRING, 1,2 * KARINA PERSIYANOV, 1,3 DIANE DUNN, 4 ROBERT WEISS, 4 ERIN L. MEYER, 3 AND SCOTT W. ROGERS 1,3 1 Salt Lake City Veterans Administration-Geriatrics Research, Education and Clinical Center, Salt Lake City, Utah 84132 2 Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84132 3 Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84132 4 Department of Human Genetics, University of Utah, Salt Lake City, Utah 84132 ABSTRACT The response by individuals to nicotine is likely to reflect the interaction of this compound with target nAChRs. However, resolving how different genetic backgrounds contribute to unique mouse strain-specific responses to this compound remains an important and unresolved issue. To examine this question in detail, expression of the nicotine acetylcholine receptor (nAChR) sub- units 3, 4, 5, 7, 2, and 4 was measured in the dorsal hippocampus using immunohisto- chemistry in mouse strains or lines BALB/c, C3H/J, C57BL/6, CBA/J, DBA/2, Long Sleep (LS), Short Sleep (SS), and CF1. The nAChRs in all mice colocalized with glutamic acid decarboxylase (GAD)-positive interneurons that were subclassified into at least four groups based on nAChR subunit heterogeneity. A notable difference between mouse strains was the expression of nAChRs by astrocyte subpopulations in CA1 subregions whose numbers vary inversely with nAChR-immunostained neurons. This novel relationship also correlated with published param- eters of strain sensitivity to nicotine. Attempts to identify the origin of this significant difference in nAChR expression among strains included comparison of the entire nAChR4 gene sequence. Although multiple polymorphisms were identified, including two that changed nAChR4 amino acid coding, none of these clearly correlate with strain-related differences in cell type-specific nAChR expression. These findings suggest that mouse strain-specific behavioral and physiolog- ical responses to nicotine are likely to be a reflection of a complex interplay between genetic factors that shape differences in expression and cellular architecture of this modulatory neuro- transmitter system in the mammalian nervous system. J. Comp. Neurol. 468:334 –346, 2004. © 2003 Wiley-Liss, Inc. Indexing terms: nicotine; mouse strains; nicotinic receptors; immunohistochemistry; hippocampus; astrocytes Nicotine has many diverse effects on the central ner- vous system including initiating mechanisms that lead to behaviors of addiction, a process that can vary dramati- cally between individuals (Pomerleau, 1995; Lerman et al., 2002). An underlying genetic predisposition to nicotine addiction is supported by the finding that mouse strains exhibit strain-specific behavioral and physiological re- sponses to this agent including the development of toler- ance to repeated drug exposure (Marks et al., 1991; Over- street, 1995; Crawley et al., 1997; Mohammed, 2000; Picciotto et al., 2001). The number of high-affinity nicotine binding sites, which varies between animals of different strains, has been suggested to account for as much as 40% Grant sponsor: National Institute on Drug Abuse (NIDA); Grant num- ber: DA015148; Grant sponsor: National Institute on Aging; Grant num- ber: AG17517; Grant sponsor: NIDA/National Heart, Blood, and Lung Institute; Grant number: PO1 HL72903; Grant sponsor: the Val A. Brown- ing Foundation. This work is in memory of John Browning. *Correspondence to: Lorise C. Gahring, Div. of Geriatrics, Dept. of Medi- cine, University of Utah School of Medicine, SOM 2C110, 50 North Medical Drive, Salt Lake City, UT 84132. E-mail: Lorise.Gahring@HSC.UTAH.EDU Received 1 May 2003; Revised 2 July 2003; Accepted 21 August 2003 DOI 10.1002/cne.10943 Published online the week of November 24, 2003 in Wiley InterScience (www.interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 468:334 –346 (2004) © 2003 WILEY-LISS, INC.