Dissecting the behaviour of transgenic mice: is it the mutation, the genetic background, or the environment?

Increasingly sophisticated and precise molecular genetic tools are applied to mice in order to study the cellular mechanisms underlying higher brain f unctions, including learning and memory. However, several studies have prod uced unclear or conflicting results. One reason for this is that performanc e in the behavioural tests used to assess learning and memory is influenced by various non-cognitive phenomena and can thus easily be affected by muta tions through mechanisms unrelated to memory function. We conducted princip al component analysis on data From 3003 mice tested using a standardized pr otocol to demonstrate this for the Morris swimming navigation Lest, one of the most widely used paradigms to assess memory and hippocampal function. I n addition, we present a meta-analysis showing that genetic background and environment alone produce sufficient variation to span the range of most, i f not all, behavioural variables and can thus easily mask or fake mutation effects if genetic studies are not designed properly. We suggest that the c hance of obtaining useful results is maximized if behavioural deficits are differentiated by combining complementary behavioural protocols and by anal ysing multiple complementary parameters in each of them. Mutation effects m ust be contrasted statistically against the influences of genetic backgroun d and environment. In many situations, this is most efficiently achieved if (i) mutations are backcrossed to and maintained in one or (preferably) two well-characterized, commonly available inbred strains and (ii) if mutant a cid wild-type littermates are analysed on a hybrid or mixed genetic backgro und, that is in F1 or F2 generations derived from the inbred stocks.