Strain Differences

The strain-specific effects on behaviour can be greater than the contributions made by a single gene, i.e. mouse strain differences can sometimes confound the results of a gene knock-out experiment. For instance, in the a6 null mutants, withdrawal hyperexcitability following chronic ethanol was markedly enhanced in the mutant 129/SvJ strain compared to controls but was unaltered in the mutant C57BLl6J (HOMANICS et al. 1998). Thus, significant differences in tests of withdrawal hyperexcitability maybe confounded by the influence of genes that cosegregate with the targeted allele.

Frequently, mutants of mixed genetic background are generated and F2-F4 generations are behaviourally tested which may retain a bias of the genetic background (JONES et al. 1997; HOMANICS et al. 1997b). For instance, an a6 null mutant of mixed background (129/SvJ x C57BLl6J) showed a stronger response to diazepam (10mg/kg and 20mg/kg) in the rotarod test than all control lines (mixed background, 129/SvJ or C57BLl6J). However, the different types of control mice differed among themselves in their drug response and thereby influenced the quantitative impact of the mutation (KORPI et al. 1998).

To minimize the influence of the genetic background, it is recommended to generate two different pure mutant lines by backcrossing for at least five, better ten or more, generations (GERLAI 1996; BANBURY CONFERENCE 1997), followed by testing both strains separately or subsequent Fl hybrids. This pro-cedure has been followed for the behavioural assessment of y2+1- mice (CRESTANI et al. 1999). Finally, many of the shortcomings of the gene inacti-vation approach to probe GABAA-receptor function can be avoided when the expression of the gene remains unaltered and the functional impairment is introduced by a point mutation. This strategy has been very successfully employed to attribute the benzodiazepine pharmacology to distinct GABAA-receptor SUbtypes (see Sect. A) (RUDOLPH et al. 1999).

Acknowledgement. I wish to express my gratitude to the collaborators who contributed to the genetic analysis of GABAA-receptor function: S. Balsiger, K. Baer, D. Benke, 1. Benson, H. Bluethmann, I. Briinig, F. Crestani, C. Essrich, 1. M. Fritschy, R. Keist, K. Low, M. Lorez, B. Liischer, I. R. Martin, C. Michel and U. Rudolph.

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