Elsevier

Neuroscience

Volume 129, Issue 3, 2004, Pages 575-582
Neuroscience

Impaired passive avoidance learning in mice lacking central neuronal nicotinic acetylcholine receptors

https://doi.org/10.1016/j.neuroscience.2004.09.003Get rights and content

Abstract

The nicotinic cholinergic system influences cognition, anxiety, locomotion, and addiction by acting upon nicotinic acetylcholine receptors (nAChRs). To date, there are 12 known neuronal mammalian nAChR subunits leading to a rich pharmacological diversity that is difficult to attribute to specific subunits. We generated α7-β2 nAChR double mutant mice by breeding to investigate the effect of a minimal number of nAChRs in the CNS. These mice have been used to determine the role these receptor subunits play in a variety of behaviors. A battery of behavioral tests was used to determine the effect of the mutation in anxiety, locomotor activity, startle response, pre-pulse inhibition, motor coordination and learning and memory. Mice lacking both the α7 and the β2 nAChR subunits displayed impaired learning and memory performance in a passive avoidance test and showed enhanced motor performance on the rotarod.

Section snippets

Mice

α7 And β2 null mutant mice were previously generated from 129/SvEv ES cells (Orr-Urtreger et al., 1997; Xu et al., 1999) and backcrossed eight times onto a C57Bl/6 background. α7β2 Double null mutant mice were generated by crossing α7−/− mice with β2−/− mice. The resulting α7±β2± mice were interbred and α7±β2+/+ or α7±β2−/− progeny were interbred. The resulting α7+/+β2+/+ or α7−/−β2−/− mice were interbred to produce test animals. Tail biopsies were taken after weaning at 3–6 weeks of age and

Results

Mice lacking both α7 nAChRs and the β2 nAChRs were generated by breeding mice with single mutations previously described (Orr-Urtreger et al., 1997; Xu et al., 1999). Double mutant mice α7−/−β2−/− were similar in weight and appearance to their wild-type, age-matched controls and could not be distinguished without genotyping using PCR (data not shown). Mice were evaluated on a battery of behavioral tests (see McIlwain et al., 2001), which included assays for locomotor activity, anxiety, motor

Discussion

We generated mice which lack the majority of nAChRs in the CNS. Mutant α7−/−β2−/− mice appeared normal in their home cage; however, they differed significantly from α7+/+β2+/+ mice in a number of ways when tested using various behavioral paradigms. Mutant α7−/−β2−/− made significantly more transitions in the light–dark test. However, the overall exploratory behavior in the open-field was similar between α7−/−β2−/− and wildtype mice. Together these data indicate that mutant α7−/−β2−/− are less

Acknowledgments

The authors wish to thank Dr. Arthur Beaudet, MD, for providing the mouse models and for support and Dr. Amir Fayyazuddin, PhD, for useful discussions and critical reading of the manuscript. The work was supported by NIDA PO1 DA12661. The authors are particularly grateful to Leah Goldberg for outstanding technical assistance.

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