Neurobehavioural genetics. Isolation and characterisation of behavioural mutations in mice

Twin and adoption studies have consistently implicated genetics in the aetiology of psychiatric and behavioural disorders. The identification of the genes and molecular pathways that are associated with these traits using linkage studies has been difficult because psychiatric disorders are almost always non-mendelian, heterogeneous, involve multiple genetic loci and are influenced significantly by environmental factors. Mouse models that are based on intermediate signatures of psychiatric disease and pharmacological responsiveness hold promise as a complementary approach to dissecting the molecular basis of neurobehavioural disorders. This has been made possible by the development and refinement of gene targeting technologies and the use of super-efficient chemical mutagens. ENU mutagenesis in the mouse, when coupled to a battery of sensitive behavioural screens is an effective way of creating and identifying novel mouse behavioural mutants. Screens for specific deficits in behaviours such as biological rhythms and learning/memory are being used in combination with molecular genetic techniques to identify and characterise genes with a behavioural function.||It is hoped that the study of mouse mutants that have arisen from these screens will provide new insights into the genetic basis of abnormal behaviour and that they might lead to the development of novel therapeutic compounds for human psychiatric disease.

Genetic approaches provide a powerful means by which to examine the biological basis of nervous system diseases such as dementias, neurodegenerative disorders and affective disorders as well as the physiological processes that are affected by them. Almost all mental illnesses are accompanied by abnormal physiological and neurological characteristics that can be readily observed in mice. Phenotype-based approaches have been used successfully in organisms such as Drosophila melanogaster in establishing a genetic basis for many behavioural processes. Use of the chemical mutagen ENU along with hierarchical screening protocols has indicated that phenotype-based approaches in the mouse will be useful in gaining a molecular insight into complex mammalian behaviours.||One of the goals of this group is to identify and characterise ENU-induced mutations that affect specific behavioural processes. The first class of mutations being screened for are those which affect the mammalian circadian clock. The circadian system can be divided into three basic components - the input or entrainment pathway, the central pacemaker and the output pathway. Disruption of any of these components could be responsible for rhythm and sleep anomalies associated with complex psychiatric disorders. Pacemaker function is generally assessed by measuring an identifiable component of the output pathway such as locomotor (wheel-running) activity. The second class of mutations being screened for are those that affect learning and memory. Using these screens, we can identify not only molecular components specifically associated with memory formation but also components associated with neural mechanisms such as migration, plasticity and degeneration.||Paradigms such as Spontaneous Alternation, Novel Object Recognition, Holeboard exploration and Attention testing screens are being used to identify potential mutants. Positional cloning of several mutations identified in these screens is currently underway. This approach is complemented by carrying out molecular analysis of novel mutations. Primarily this involves histological analysis and in situ hybridization of brain regions suspected to be associated with particular behaviours. For example, circadian rhythms are associated with a brain region called the suprachiasmatic nucleus, located in the hypothalamus and consisting of approximately 10,000 cells. Histological analysis tells us whether there is a gross dysmorphology associated with the mutation, indicating that underlying neurodevelopmental processes might be affected.||In addition, by using specific molecular markers known to be associated with a particular behaviour, we can determine the molecular consequences of each mutation. Systematic approaches to characterising molecular pathways associated with behavioural traits are being established.