Banbury Conference on Genetic Background in Mice*identity of the genetic elements governing these other factors (modifiers) is usually unknown, it is important to keep them constant when evaluating the impact of a Mouse mutants derived by targeted mutagenesis in emmutation. Only if the same genetic background is used bryonic stem (ES) cells offer many advantages to the across experiments can differences between the phenostudy of the molecular and cellular mechanisms underlytypes obtained be ascribed to the mutations rather than ing behaviors such as learning and memory, circadian to different genetic backgrounds. Adoption of a comrhythms, motor coordination, and aggression, as well mon genetic background does not preclude comparison as other neuroscience research areas such as brain of the effects of a given mutation in different backdevelopment. The beginning of any new field, however, grounds. is often marked by a period in which key issues are Genetic background can be used as a tool in the debated, and as a consequence the approach is sharpanalysis of a mutation (e.g., quantitative trait loci analyened and focused. Theoretical and practical issues resis and enhancer/suppressor screens; Takahashi et al., lated to the impact of genetic background on the analy-1994). By placing the same mutation in different genetic sis of mutant mice have been a central topic of backgrounds, it is possible to study facets of gene funcdiscussion in this new field (Crawley, 1996(Crawley, , 1997 Crusio, tion that would elude studies in any single background. 1996;Gerlai, 1996;Lathe, 1996;Wehner and Silva, 1996).Additionally, powerful new mapping and cloning strate-Analysis of the literature reveals that there is no consengies may allow the identification of modifiers from differsus on the nature of appropriate controls for genetic ent backgrounds (Dietrich et al., 1993; Gould et al., background. This report summarizes a recent Banbury 1996). Genetic interactions between a mutation and the workshop held in Cold Spring Harbor, New York, on genetic background may account for the variable pene-December 8-11, 1996, to discuss these issues in an trance of human genetic diseases, and it is important effort to come to a consensus within the field. The recto study and understand the nature of these interactions. ommendations that follow reflect the need for rigorously Most targeting experiments to date have relied on controlling the genetic background of experimental anithe use of ES cells derived from substrain 129 mice. mals, and the practical issues surrounding the imple-However, the 129 substrains are a complex collection mentation of the appropriate controls.

Voltage-gated potassium channels (Kv) of the Shaker-related superfamily are assembled from membrane-integrated alpha subunits and auxiliary beta subunits. The beta subunits may increase Kv channel surface expression and/or confer A-type behavior to noninactivating Kv channels in heterologous expression systems. The interaction of Kv alpha and Kv beta subunits depends on the presence or absence of several domains including the amino-terminal N-type inactivating and NIP domains and the Kv alpha and Kv beta binding domains. Loss of function of Kv beta 1.1 subunits leads to a reduction of A-type Kv channel activity in hippocampal and striatal neurons of knock-out mice. This reduction may be correlated with altered cognition and motor control in the knock-out mice.

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Long-term memory (LTM) requires activation of the transcription factor cAMP-responsive element binding protein (CREB). Signaling by the Ca2+/calmodulin (CaM) kinase cascade has been implicated in CREB activation and memory consolidation processes in the hippocampus. The CaM kinase kinase beta isoforms belong to the CaM kinase cascade, and we have generated null mutant mice to investigate the role of these kinases in several forms of learning and memory. The null mutants were impaired in spatial training-induced CREB activation and spatial memory formation. Furthermore, the mutants lacked late, but not early, long-term potentiation at the hippocampal CA1 synapse, and they were impaired in LTM, but not short-term memory, for the social transmission of food preferences. We suggest that the CaM kinase kinasebeta isoforms are required for the formation of hippocampal LTM. Surprisingly, however, these kinases were not needed for contextual, trace fear, and passive avoidance LTM. Our results demonstrate that different signaling processes underlie the formation of these types of hippocampal LTM.