N-ethyl-N-nitrosourea mouse mutants in the dissection of behavioural and psychiatric disorders
Section snippets
The mouse as a model of psychiatric disease
Twin and adoption studies have implicated genetics in the aetiology of attention-deficit hyperactivity disorder, autism, bipolar disorder, depression, anxiety disorders, and schizophrenia Folstein and Rutter, 1977, Heston, 1966, McGuffin et al., 1996, McGuffin et al., 2003, Rietveld et al., 2003. Yet, despite the great advances that have been made in genetics in the last 50 years, the underlying causative factors remain largely unknown. Many groups have undertaken linkage studies to identify
Spontaneous mouse mutants
The study of spontaneous mouse mutants has led to important insights into gene function and disease phenotypes. An example of a spontaneous mutant relevant to psychiatric disorders is the mouse mutant coloboma. Coloboma was first identified because it exhibited head bobbing, hyperactivity and ocular dysmorphology (Hess et al., 1992), and was later shown to exhibit altered hippocampal plasticity (Steffensen et al., 1996) and neurodevelopmental abnormalities (Heyser et al., 1995). Genetic mapping
Gene targeting and reverse genetics
The use of homologous recombination in embryonic stems cells has permitted scientists to generate targeted mutations in specific genes. This approach is referred to as reverse genetics, as one begins with a particular hypothesis about the function of a gene and proceeds to study the phenotypic consequences of a targeted mutation in that gene. Gene targeting has revolutionised mouse behavioural genetics, playing a vital role in the understanding of the molecular basis of memory Reisel et al.,
Chemical mutagenesis and forward genetics
Forward genetics differs from reverse genetics, as it begins not with an interest in a particular gene, but in a phenotype (e.g., an abnormal behaviour). Relying on chemical mutagenesis to produce random mutations, forward genetics has been used extensively in several species to study gene function by establishing screens for various phenotypes Driever et al., 1996, Nusslein-Volhard and Wieschaus, 1980. Pioneering studies in screening specifically for behavioural mutants were introduced by
The case for ENU
The chemical mutagen N-ethyl-N-nitrosourea (ENU) has been established as the most appropriate mutagen for gene function studies in the mouse. This preference is based on several properties specific to ENU. Firstly, ENU induces mutations in rodents at a rate that is far greater than that of other mutagens. Several groups have estimated that phenotypic effects associated with every mammalian gene could be detected by screening only ∼1000 animals carrying ENU-induced mutations Coghill et al., 2002
Implementing an ENU mutagenesis screen
A number of institutes worldwide have established mouse ENU mutagenesis screens with the goal of modelling human disease and prescribing a function to each mammalian gene. Many groups have incorporated screens for behavioural phenotypes (See Table 1). The simplest form of screen that can be carried out is one for dominant ENU-induced mutations. With this approach, males are treated with ENU and subsequently mated with wild-type females (Fig. 1). Progeny from these crosses, which can each
Mouse mutants and anxiety
A number of mouse paradigms have been developed to explore the biological basis of anxiety. The most widely used are the open field, elevated plus maze and dark–light box (Rodgers, 2001). These devices all rely on the innate aversion of mice to open spaces and bright areas, which conflicts with their natural tendency to explore novel environments. An open field is a large square or round arena that is brightly lit and is normally white in colour. When placed in this environment, mice
Mouse mutants and circadian behaviour
Circadian behaviour incorporates the regulation of diverse processes such as the sleep–wake cycle, locomotor activity, temperature regulation, metabolism, water/food intake and levels of circulating hormones. This behaviour is normally synchronised to external environmental cues such as sunrise/sunset, a process known as entrainment. However, in the absence of such cues, these inherent rhythms persist. Disturbances in circadian parameters have been associated with a number of psychiatric and
Histology and pathology
Human studies have implicated abnormal brain pathology in psychiatric illness. For instance, reduced hippocampal volumes have been observed in schizophrenic patients Pegues et al., 2003, Velakoulis et al., 1999, glial cell reduction in the prefrontal cortex has been associated with mood disorders (Ongur et al., 1998) and asymmetry of the caudate nucleus has been linked to ADHD Filipek et al., 1997, Hynd et al., 1993. Given these observations, histological and pathological studies of mouse
Conclusion
The use of forward genetics approaches, such as ENU-mutagenesis screening, to identify mouse behavioural mutants is still in its infancy although results from systematic screens would suggest that this approach is valid in identifying and elaborating upon mammalian gene function. To date, no phenotypic screen has been unsuccessful in identifying novel molecular components and mechanisms. As more sophisticated phenotypic screening tools are developed, it should be possible to identify and study
Acknowledgments
DAK is supported by a Christopher Welch Scholarship for some of this work.
References (126)
- et al.
Functional identification of the mouse circadian Clock gene by transgenic BAC rescue
Cell
(1997) - et al.
Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock
Neuron
(2001) - et al.
Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia
Schizophr. Res.
(2001) - et al.
Mutation of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (lh) mouse
Cell
(1997) - et al.
Genetic basis of anxiety-like behaviour: a critical review
Brain Res. Bull.
(2002) Neuropharmacologic specificity of a simple animal model for the behavioral actions of benzodiazepines
Pharmacol. Biochem. Behav.
(1981)- et al.
Absence epilepsy in tottering mutant mice is associated with calcium channel defects
Cell
(1996) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?
Trends Neurosci.
(1996)- et al.
Mapping quantitative trait loci for fear-like behaviors in mice
Genomics
(1997) - et al.
Coloboma hyperactive mutant exhibits delayed neurobehavioral developmental milestones
Brain Res. Dev. Brain Res.
(1995)