Human Molecular Genetics, 2000, Vol. 9, No. 6 893-900
© 2000 Oxford University Press
Towards new models of disease and physiology in the neurosciences: the role of induced and naturally occurring mutations
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, UK and 1MRC Mammalian Genetics Unit and Mouse Genome Centre, Harwell OX11 0RD, UK
Received 7 February 2000; Accepted 9 February 2000.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSPONTANEOUS MOUSE MODELS OF...APPROACHES TO CREATING NEW...N-ETHYL-N-NITROSOUREA (ENU)...IMPLEMENTATION OF APPROPRIATE...CONCLUSIONSREFERENCES |
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There is a dearth of good mouse models for central nervous system (CNS) disorders. However, the development of gene-targeted technology and the recognition of the importance of the mouse as a model organism have led to the development of a range of behavioural tests for mice. Spontaneous mutations in mice have already provided important information about the role of novel gene products in disorders such as epilepsy and deafness. This has provided the impetus to the establishment of large-scale mutagenesis programmes to generate new mutations. Tests of sensory and motor function have previously been most frequently used as these are simple to perform and the phenotypes are relatively obvious. Subtle phenotypes, of relevance to pyschiatric disorders such as anxiety and schizophrenia, can be detected using more complex tests. Screens such as prepulse inhibition and startle have been adapted for mice and these can be run with relatively high thoughput using fully automated equipment. Other behaviours such as sleep and circadian rhythms, learning and memory and nociception can also be assessed. New technological advances in non-invasive imaging and neurochemical analyses have meant that these techniques can be readily applied to mouse phenotyping. The use of these screens together with mutagenesis is already beginning to increase the numbers of mouse models of potential relevance to CNS diseases.
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INTRODUCTION |
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Despite recent advances in our understanding of the molecular basis of some central nervous system disorders, there is still an enormous number of human diseases for which we do not have a clear idea of the underlying molecular pathology. There are three developments that presage major advances in our understanding of the underlying genetic lesions for neurological disease. First, the completion of the genome sequences of human and mouse will give us unprecedented access to a comprehensive and annotated database of all genes in the mammalian genome (1). At the same time, access to massively parallel methods of gene expression analysis (expression profiling) through the use of microarrays will enable us to document in a comprehensive and systematic fashion patterns of gene expression in normal and diseased states (2). Finally, mutagenesis approaches will allow us to relate both gene and expression information to phenotype and function (3). It is, however, mutagenesis that will be key to ascribing and defining function. For this reason, the development of comprehensive mutant archives in model organisms, in particular the mouse, will be vital if we are to dissect the genes and pathways that are critical for neurological development and function. Indeed, where advances in our knowledge of the aetiology and treatment of a disease have been made, these have usually involved the use of either induced or naturally occurring mutations in mice to model the disorder in man. However, for many neurological and behavioural disorders, e.g. schizophrenia and depression, no good animal models exist. We discuss here some of the approaches that are being taken in the area of neurological disease to close this phenotype gap.
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SPONTANEOUS MOUSE MODELS OF NEUROLOGICAL DISEASE |
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Spontaneous mutations in mice have already been shown to be of value in understanding the physiology of both normal and disease states in neurological systems. A recent example is work carried out using the stargazer mouse (4). This mouse is one of several spontaneously arising mutations in mice that give rise to spike wave epilepsy. The electroencephalograms (EEGs) of these mice closely resemble those seen during absence seizures in man. Positional cloning of the stargazer gene showed that it encoded a
subunit of neuronal voltage-operated calcium channels (VOCCs). Thus, not only were VOCCs shown to be important in mediating the epileptogenic phenotype, but also the existence of a neuronal subunit was uncovered. The subunit had previously only been seen in channels from muscle tissue, despite extensive probing for a neuronal isoform. Indeed, ion channel mutations have been amongst the most successfully investigated with regard to spontaneous mutations as two other mouse mutant strains, lethargic and tottering, have mutations in genes encoding 
1A and ß subunits, respectively (5,6). Thus, the utility of naturally occurring mouse mutants for neurological disorders has been validated. Other examples where the cloning of spontaneous mutants has provided novel insight into neurological disease include the myelin mutants, e.g. trembler (7) and jimpy (8), and sensorineural deafness mutants, e.g. shaker1 (9), Snell’s waltzer (10) and shaker2 (11). A search of the current Mouse Genome Database (www.informatics.jax.org ) uncovers 197 mutations with a neurological or neuromuscular phenotype, excluding deaf and circling mutations (many of which will be due to a vestibular lesion). In addition, 37 mutations were identified with a behavioural phenotype. Nevertheless, the current mouse mutant archive contains mutations at only a small fraction of the total number of mammalian genes and this is true as much for neurological and behavioural models as for mutants affecting other systems (12). |
APPROACHES TO CREATING NEW MOUSE MODELS FOR NEUROPHYSIOLOGY AND BEHAVIOUR |
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There are several methods for producing new mouse mutant models, as documented in Table 1. These approaches fall basically into two categories: genotype and phenotype driven. Genotype-driven approaches include transgenic methodologies, as well as the use of gene targeting through the use of homologous recombination in embryonic stem (ES) cells. On a genome-wide scale, genotype-driven approaches also encompass the creation of gene trap libraries in ES cells (13). ES cell lines carrying a disrupted transcription unit can be selected from the gene trap library and mutant mice derived for phenotyping. Extensive literature exists on the generation and characterization of gene-targeted and transgenic mice in behavioural and physiological paradigms (14,15). Some examples where these are of relevance to human disease are shown in Table 2. Owing to space constraints, the fruits of these genotype-driven approaches will not be considered further here, although a number of issues that have been identified in working with such mice are common to mice derived from phenotype-driven approaches (16). Instead, this review will focus on the potential of phenotype-driven approaches to provide new mouse models of human disease.
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The disadvantage of genotype-driven approaches to mutagenesis is that they require a priori assumptions to be made concerning the function and likely phenotype of the mutated gene. In contrast, phenotype-driven approaches to mutagenesis take as their starting point the recovery of novel phenotypes. No assumptions need to be made about the genes underlying a particular system and, for this reason, phenotype-driven approaches should be a powerful route to identifying novel gene function and uncovering novel gene pathways (17).
Phenotype-driven mutagenesis has classically employed chemical mutagenesis to introduce random mutations around the genome efficiently followed by the application of appropriate screens to recover relevant phenotypes. These approaches have previously been employed extensively in non-mammalian species, most notably Drosophila and the zebrafish (18,19). In Drosophila, phenotype-driven approaches have been taken to the height of sophistication, whereby the mutagen is a transposable element, the P-element containing Gal4 upstream activating sequences (20). Many independent target lines can be screened in any system of interest for the phenotypic consequences of misexpression of mutated genes by crossing to a line expressing Gal4. These non-mammalian model systems have been invaluable for the genetic dissection of some of the key molecular components underlying certain neurological pathways. For example, Drosophila mutants have played a pivotal role in identifying some of the key components of the circadian rhythm pathway (21). However, non-mammalian species have clear limitations when exploring the genetic basis of complex behaviour and neurophysiology. For this reason, we can expect the mouse to be the organism of choice for systematic exploration of mammalian gene function and its impact on neurology and behaviour. For this reason, a number of large- and small-scale mutagenesis programmes are under way focused on the recovery of neurological mutations (Table 3).
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N-ETHYL-N-NITROSOUREA (ENU) MUTAGENESIS FOR THE GENERATION OF NEW NEUROLOGICAL AND BEHAVIOURAL MODELS IN THE MOUSE |
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ENU is the preferred chemical mutagen in mice as it induces point mutations at high frequency. Specific locus mutation frequencies can be as high as 1.5 x 10–3 (22). Potentially, ENU can generate loss-of-function, hypomorphic, dominant-negative as well as gain-of-function mutations, and from this perspective it is a powerful tool for eliciting novel phenotypes at multifarious loci. The strategies for employing ENU to recover dominant or recessive mutations have been described elsewhere (17,22). Mice produced from ENU mutagenesis are screened in tailored behavioural, biochemical or other tests of relevance and outliers (usually 3 SD from the population mean) are then assessed for inheritance of phenotype. Small-scale ENU mutagenesis programmes have already demonstrated the potential of a more systematic approach to the production of mouse models of relevance to human neurological disease. For example, even relatively modest mutagenesis efforts have been very successful in recovering novel circadian rhythm disorders (23,24). Large-scale mutagenesis programmes are now under way in a number of centres in Europe, the USA and Japan. The success of these programmes in detecting novel mutations of relevance to neuroscience is critically dependent on the phenotypic screens employed. It is no accident that most existing documented mutations have a very obvious, usually motor, phenotype. If we are to model complex disorders such as schizophrenia, it is likely that we will have to break down the disease into its component parts, both pathologically and symptomatically, and screen for effects on these components.
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IMPLEMENTATION OF APPROPRIATE SCREENS TO IDENTIFY NEUROLOGICAL AND BEHAVIOURAL PHENOTYPES IN MICE |
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One of the most important aspects of any phenotype-based programme is the selection of screens that will provide the researcher with appropriate mutants/models in the most time-efficient manner. There is no limit to the number or complexity of screens that can be employed in such a programme. However, several points must be addressed prior to undertaking a laborious series of phenotypic screens. These points are particularly relevant in the case of behavioural and neurological screens, which are often extremely labour intensive. The first is to select tests where the performance of an individual can readily be distinguished from that of the screening population. In essence, this requires that the results of a screen exhibit as little variability as possible. Secondly, in particular when large-scale screens are being undertaken, screening procedures to identify mutants should be relatively easy to carry out. Clarification of the phenotype detected in these screens can subsequently be verified and refined in more complex functional studies. Such a hierarchical screening procedure has been proposed by Rogers et al. (25): SHIRPA. We have used this procedure in a large-scale collaborative mutagenesis programme in the UK (collaboration between SmithKline Beecham, Medical Research Council, Imperial College and Queen Mary and Westfield College).
This procedure starts with simple observational assessment from birth through to semi-quantitative screening at ~5 weeks of age (26). To date, in our collaborative UK mutagenesis programme ~20 000 mice have been assessed in this manner. Examples of mutants identified by observational assessment alone include five lines with tremor, eight lines with craniofacial anomalies and ten lines with circling/headweaving behaviour. Additional phenotypes identified have also yet to be tested. The severity of mutant phenotypes has subsequently been refined using the semi-quantitative SHIRPA screen. Analysis of data from this screen provides a comprehensive profile and can indicate deficits in muscle and lower motorneuron, spinocerebellar, sensory, neuropsychiatric and autonomic function. The screen, involving a battery of up to 40 simple tests, can be carried out in ~10 min. As well as quantifying or identifying neurological and behavioural anomalies associated with the mouse lines described above, additional classes of mutation have been catalogued using this procedure. From the ~11 000 mice that have been screened to date from the UK mutagenesis programme, we have identified 15 lines on the basis of their activity status, 11 lines with abnormal gait or ataxia and 2 lines with a lowered muscle tone. Again, additional abnormal phenotypes remain to be tested for inheritance.
Information obtained from this initial assessment can be used in several ways. First of all, this can be used to give an indication of the overall severity of a particular mutation that is characterized in other functional screens. An example of this would be to establish the motor function of targeted mutations that are deficient in a memory/learning paradigm that requires co-ordinated motor activity. In addition, the assessment can be used to select subsets of mice that are likely to be associated with a particular functional abnormality. In many cases, abnormal behaviour associated with more complex screens can be predicted using this assessment.
Rotarod performance
An accelerating rotarod paradigm can be used to characterize further mice with motor dysfunction or with peripheral nerve dysfunction. This test simply involves placing a mouse on an accelerating rotating drum and measuring the time that the mouse can remain on the drum. As this test requires motor co-ordination, several retests may be required before an accurate profile can be established. In the current UK mutagenesis programme, the behaviour of a number of gait/ataxia and tremor mutants has been found to be compromised in the rotarod test.
Locomotor activity (LMA)
Monitoring LMA in mice can be used to identify models of anxiety disorders as well as deficits in motor function and abnormally high activity levels (27,28). Automated activity recording can be carried out using infrared beam-splitting equipment (26). The number of beam splits and the number of cage transitions over a certain period of time can be recorded and analysed automatically. In the simplest case, total activity and cage transitions are measured over a 30 min period. Approximately 0.5% of mice screened in the current UK mutagenesis programme to date have abnormal LMA scores. It is interesting to note that mice expressing particular phenotypes (e.g. circling) are extremely active in LMA. Figure 1 shows how LMA scores can be quantified for a particular mutant mouse line. This line did not exhibit any circling behaviour, but did return scores in the initial phenotypic assessment that suggested hyperactivity.
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Acoustic startle response (ASR) and prepulse inhibition (PPI)
The ASR is characterized by an exaggerated flinching response to unexpected auditory stimuli. This response can normally be attenuated when it is preceded by a prestimulus: PPI. Lowered PPI values have been associated with a number of human psychiatric disorders, including schizophrenia (29), and recently mouse models with single-gene defects exhibiting lowered PPI scores have been identified and characterized (30,31). The screen for potential mouse mutants has been described earlier (26). Briefly, mice are housed in soundproofed startle chambers. They are subjected to a series of sound pulses (ASR) and again subjected to these sound pulses coupled with weaker prepulses (PPI). Responses to the sound pulses are automatically recorded using an accelerometer linked to a PC. Responses are expressed in arbitrary units and averaged for each type of sound stimulus. In either of these tests, ~0.5% of mice screened in the UK mutagenesis programme have exhibited abnormal scores. For both these and the locomotor tests, it is important to retest the animals to confirm any abnormal phenotype as our current screening programme has shown that <25% of abnormal scores are confirmed on retest.
Learning and memory
A number of tests of learning and memory have been fully characterized and validated for mice.
The water maze.
In this test, mice have to locate a hidden platform in a circular pool of water using distal cues around the pool (for methods see ref. 32). Typically, training takes place over several days with up to six trials per day. At the end of training, animals are tested with a visible platform in the pool to check for any non-specific effects, e.g. on visual acuity, motivation to escape the water. This is a test of spatial reference memory, which is strongly dependent on intact hippocampal function. Non-spatial protocols have also been developed (33). The spatial variant of the test has been used extensively with transgenic mice (34–36). In-house and published data have shown that there are wide variations between strains of mice in their ability to learn the task (32,37).
Radial arm maze.
This is another spatial learning test, but it is appetitively, rather than aversively, motivated, i.e. food or water reinforcement is used. The maze consists of a number of arms (usually eight) radiating out from a central arena. At the end of each arm is a food reward and the test can be configured to study spatial working memory alone by rebaiting all the arms on each trial (38). To study both working and reference spatial memory, the test is configured slightly differently. Here for every trial, the same four arms remain unbaited—visits to these arms will be reference memory errors. The remaining four arms are baited on each trial. Visits to one of these arms after the initial visit will be working memory errors. This test has been used to show impairments in memory in transgenic and knockout (KO) mice.
Avoidance tests.
Several types of avoidance test exist. Passive avoidance is a relatively easy test to carry out and could be incorporated into a large-scale screening programme. However, the data from this type of test can be hard to interpret. In this test, animals are placed in the light compartment of a two-compartment box. The other compartment is dark and contains a grid floor through which a brief electric current can be passed. The mouse passes into the dark compartment (as mice prefer the dark), where it receives a brief foot shock. Memory is assessed by recording the latency to entering the dark compartment if the mouse is replaced, after a period of time, in the light compartment. However, a number of factors, e.g. anxiety level, shock sensitivity etc., can alter performance on this test, so these confounding variables have to be ruled out before a direct effect on memory can be inferred. In a conditioned avoidance task, the animal has to move actively from one compartment to another to avoid getting a shock. The onset of the shock follows a cue—the conditioned stimulus—and the animal has to learn the association between the cue and the shock. Again, these tests have been used to assess function of transgenic and KO mice, and wide variations in performance on these tasks exist between different mouse strains (37,39).
Anxiety and anti-depressant tests
Although SHIRPA has measures of emotional reactivity in the test, specific tests do exist for anxiety in mice. These include the holeboard and the elevated plus maze tests. The elevated plus maze is a relatively simple test and consists of four arms elevated above the floor: two arms are enclosed and two are open. Anxious animals spend more time in the enclosed arms and rarely venture out onto the open arms. Anxiolytic agents increase the percentage of time that the animal spends on the open arms (36). Detailed methodologies for both the holeboard and elevated plus maze tests for mice are described by Rogers et al. (32). Another test in mice which does not require any prior training is the black/white box (40). Here, the percentage of time that the mouse spends in the white box is indicative of the level of anxiety of the mouse. The social interaction test, which has been used in rats to measure anxiety, is not suitable for use with mice.
The most extensively used anti-depressant test in mice is the forced swim test, where the mouse is placed in water and allowed to swim. Initially, the mouse swims vigorously for a short period, but if it cannot escape it adopts an immobile posture. An anti-depressant-like action is reflected by a reduction in the time spent immobile. A review of the procedure is provided by Evenden et al. (41).
Nociception
Simple tests of pain perception can be used in mice to follow up on the preliminary data obtained in the SHIRPA screen (toe pinch). The simplest test to use is the hotplate. The temperature is usually set at 50°C, although temperatures up to 55°C can be used. Mice are placed on the hotplate and the latency to performing either hindpaw lick or hindpaw shake/fanning recorded. This and other nociceptive tests in mice are comprehensively described by Mogil et al. (42).
Wheel-running activity: circadian rhythms and entrainment
Abnormalities of the sleep–wake cycle and associated circadian rhythms have been observed in many psychiatric disorders, including seasonal affective disorder (SAD), depression, bipolar disorder and schizophrenia (43–45). Circadian clocks regulate diverse processes such as the sleep–wake cycle, locomotor activity, temperature regulation, metabolism, water and food intake, adrenal corticosterone levels and ageing. Endogenous clocks are normally synchronized to a 24 h cycle by external environmental cues such as light, known as entrainment. However, in the absence of such cues, these inherent rhythms persist. Major advances in the genetic basis of pacemaker function in rodents have been made recently by the identification of the mouse Clock mutation (46). In rodents, wheel-running activity is used to study circadian activity. Under light–dark (LD) conditions, an animal’s wheel-running activity is entrained to the lights-off stimulus, with the activity phase () occurring during the dark period. When transferred to constant darkness (DD), the animals free-run with a periodicity reflecting the activity of the endogenous pacemaker. The onset of the activity phase is highly regular under DD conditions (47). Pulses of light can reset this activity onset depending on the point of the cycle at which the light pulse is given. By screening for mice where this activity is not reset, it may be possible to gain an insight into mechanisms of photic entrainment. Although one drawback with wheel-running activity screens in the mouse is the time and effort involved in identifying and characterizing new mutants, it is ultimately rewarding since it will uncover novel components of the complex circadian system in mice and humans.
Neurochemical analyses
Clearly, many neurodegenerative conditions produce alterations in sensorimotor behaviour that can be readily observed. However, some neurodegenerative diseases need more sophisticated behavioural screens to pick up changes, e.g. dementia or schizophrenia. For other neurological and psychological disorders, there are no good tests of symptomatology. The involvement of various neurochemical systems in the brain in these disorders has been surmised on the basis of both post-mortem studies and drug treatment effects (48). Thus, an underactivity of both serotonergic and noradrenalin systems has been hypothesized to be involved in mediating depression, whereas an overactivity of dopamine and glutamate systems may mediate schizophrenic behaviour. Changes in glutamate and other excitatory acids have also been observed as a consequence of neurodegeneration. Currently, neurochemical analyses are being carried out on lines that have shown either gross or subtle behavioural changes. In the current UK consortia mutagenesis programme, samples are taken from six key brain regions: frontal cortex, hypothalamus, hippocampus, striatum, nucleus accumbens and cerebellum. Several mutants from the existing programme have been found to have abnormal levels of dopamine and serotonin turnover (49). Further studies looking at microdialysis in freely moving animals may link these changes with behavioural alterations indicative of a potential pyschiatric disease model.
Imaging
In addition to X-ray analysis (conventional or computed tomography) for structural abnormalities in bone, non-invasive imaging can be used to screen mutant mice. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) are non-invasive imaging techniques that have an important place in phenotypic characterization preclinically. Recently, the resolution of MRI and PET has increased sufficiently to enable their use in mice. Diffusion-weighted, T2- and perfusion-weighted NMR techniques can be used to image oedema, structural changes and blood flow, respectively (50,51). A normal T2-weighted image is shown in Figure 2a. Such imaging techniques have been used to characterize abnormalities in brain in transgenic and mutant mice (52–54), and to characterize central inflammation in mouse models (55). Thus, structural changes such as enlarged ventricles can be observed as shown in Figure 2b, and animals can be repeatedly imaged over time to assess whether further changes occur. Additionally, MRI has been used for imaging eye development in strains where spontaneous abnormalities in the eye occur (56).
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For PET, current animal scanners still have low resolution relative to the size of a mouse and this can lead to difficulty in quantitating data from mouse PET images. Fluorine-18-fluorodeoxyglucose is the most common radioligand used to study oxygen utilization and hence assess which areas of the brain are activated (57). Unlike people, the animals are anaesthetized, so only effects on basal metabolism under anaesthesia can be examined. Other workers have used the peripheral benzodiazepine receptor ligand [3H]PK11195 as a marker of activated microglia and macrophages, which could be useful in screening for neurodegenerative changes (58).
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It can be seen from the above that it is an exciting time for mouse behaviouralists and neurogeneticists. ENU mutagenesis, coupled with the rapid increase in our knowledge of the mouse genomic sequence, is providing an efficient route to novel phenotypes and genes. Screens for neurological and behavioural effects in mice are now becoming well established and are already being used in large-scale screening programmes such as the UK mutagenesis programme. Future developments may see the incorporation of new screens, perhaps those involving pharmacological or other types of challenge, together with the use of different genetic backgrounds to look for modifier effects. However, the existing programmes have already borne fruit in terms of interesting new phenotypes, which may give us important clues to the aetiology of central nervous system diseases that have been hard to dissect in man.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +44 1279 622341; Fax: +44 1279 622660; Email: a_jacqueline_hunter@sbphrd.com
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REFERENCES |
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