Human Molecular Genetics, 2000, Vol. 9, No. 6 953-965
© 2000 Oxford University Press
Dissection of behavior and psychiatric disorders using the mouse as a model
1Center for Neurobiology and Behavior, Department of Psychiatry and 2Department of Genetics, University of Pennsylvania, CRB, 415 Curie Boulevard, Philadelphia, PA 19104, USA
Received 28 January 2000; Revised and Accepted 8 February 2000.
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ABSTRACT |
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 TOP ABSTRACT MOUSE MODELS FOR HUMAN...‘GOOD GENETICS NEEDS GOOD...IDENTIFICATION OF BEHAVIORAL...REFERENCES |
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Mouse genetic models have played an important role in the elucidation of molecular pathways underlying human disease. This approach is becoming an increasingly popular way to study the genetic underpinning of psychiatric disorders. Genes within candidate regions for susceptibility to psychiatric illness can be evaluated through the phenotypic assessment of mutants mapped to the corresponding regions in the mouse genome. Alternatively, one can search for mouse mutants displaying characteristics that might correspond to physiological and behavioral markers of a psychiatric disorder, sometimes referred to as endophenotypes. Mice with anomalies in these traits can be generated by targeted mutagenesis in known genes (gene-based mutagenesis or reverse genetics), or can be identified among progeny of mice in a random mutagenesis screen (phenotype-based mutagenesis or forward genetics). In this review, we discuss recently generated behavioral mutants in the mouse. We also give an overview of several robust and commonly used behavioral phenotypes, their relevance to human disease and lessons learned from recent successes in mouse behavioral genetics.
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MOUSE MODELS FOR HUMAN BEHAVIORAL AND PSYCHIATRIC DISORDERS |
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TOPABSTRACTMOUSE MODELS FOR HUMAN...‘GOOD GENETICS NEEDS GOOD...IDENTIFICATION OF BEHAVIORAL...REFERENCES |
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The burgeoning interest in the genetics of complex traits, including behavior, has generated a variety of new approaches for uncovering the genetic basis of neuropsychiatric diseases such as schizophrenia and bipolar disorder (1). Recent efforts to localize susceptibility genes through linkage strategies, including genome-wide searches, have provided evidence for possible linkage of schizophrenia to chromosome regions 6p24, 8p, 13q32, 18p11.2 and 22q11 (2–7), and for confirmed susceptibility loci for bipolar disorder on chromosomes 4p16, 18p11.2, 12q24, 13q32, 21q21, 22q11–13 and Xq26 (8–15). The observed overlap of susceptibility loci for both bipolar disorder and schizophrenia on several chromosomes (e.g. 13q32, 18p11.2, 22q11) represents an intriguing finding considering the overlap in diagnosis of schizoaffective disorders and recurrent unipolar illness in relatives of individuals with either bipolar disorder or schizophrenia (16–18).
Despite these successes in genomic localization of susceptibility loci for several common psychiatric illnesses, genome scans generally do not have the power of assigning disease susceptibility loci to narrow ‘critical’ regions, implying that the analysis of candidate genes will be a critical step in the identification of genes underlying the syndrome. Promising candidate genes and corresponding proteins are routinely identified from their physiological and pharmacological properties and from functional studies of the gene in model organisms (Fig. 1). Genetic approaches currently available in the mouse make this model organism particularly powerful in the functional analysis of candidate genes and in defining molecular pathways underlying the pathogenesis of human disease. For example, functional analysis of genes in the velocardiofacial syndrome region on 22q11, a region of shared susceptibility for bipolar disorder and schizophrenia, involves behavioral studies of mice with mutations in genes within this region (19,20).
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An alternative approach to identification of genes that may contribute to psychiatric illness involves genetic dissection of complex phenotypes into components, called endophenotypes, that may be more amenable to genetic studies than the fully expressed psychiatric manifestation of a disease (Fig. 2). For example, in schizophrenia, abnormalities in social interaction, attention, sensorimotor gating and olfactory and cognitive dysfunction have been suggested as useful endophenotypes (21–25). These neurobiological or physiological characteristics of an apparently polygenic illness may occur as the result of single gene effects and might be useful as additional and perhaps more easily measured and robust phenotypes in genetic linkage analysis (26–28).
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In this review, we suggest that these same physiological and neurobiological endophenotypes can be monitored or measured in an animal model organism. We also review and discuss current efforts to identify single gene mutations in the mouse which alter these traits. Genetic mapping of these mutant loci and predictions of their map location in the human genome based on syntenic regions in the mouse, may provide candidate genes for susceptibility loci in human disease. Even in cases where this is not so, these single gene mutations may still be valuable in providing an entry point into important genetic pathways underlying human physiology and behavior. In the field of obesity research, this point can be illustrated with the example of single gene mutations in the leptin and leptin receptor genes that cause obesity in the mouse (29–31). Although genome scans in human families segregating obesity did not identify these loci as having a major effect in the majority of families (32–36), the studies in mice provided important information about the basic physiology and regulation of body weight in both humans and rodents (37,38).
A number of strategies are currently being employed to generate or identify single-gene behavioral mutants in the mouse. A collection of mice with targeted null-mutations in known genes are increasingly used as tools for defining the in vivo function of molecules. These targeted null-mutations continue to provide a rich source of behavioral phenotypes (Table 1). In addition, the recent employment of sophisticated tools for the generation of conditional mutants exhibiting gene loss in a temporally and spatially restricted manner, is proving particularly useful in the understanding of behavior (39,40). In general, phenotypic changes in conditional mutants are more specific and subtle than in loss-of-function mutations of the same gene and, therefore, allow better understanding of underlying behavioral, neuropathological or physiological consequences. Conditional mutations also allow for more appropriate controls to dissect components of behavior such as acquisition, consolidation, retention and performance in studies of learning and memory (41,42). In the case of genes that play a role in both development and behavior, conditional and induced mutations permit studies of behavior apart from the role that the disrupted gene plays during the course of pre- or postnatal development. For example, later in this review we describe specific behavioral and electrophysiological defects in a conditional knockout for the neurotrophin tyrosine kinase receptor, TrkB (43), whereas complete loss of function of this gene is associated with postnatal lethality, most likely due to respiratory failure (44).
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In contrast to gene-based approaches, also called reverse genetics, forward genetics in an animal model begins with the phenotype. There are two approaches commonly used in forward genetics, identification of an altered phenotype due to point mutations induced by a mutagen, such as N-ethyl-N-nitrosourea (ENU) or observation of natural phenotypic variation in a genetic cross between two inbred strains to identify quantitative trait loci (QTL) (45). The intended outcome of both is the identification and positional cloning of the altered or influential gene. The QTL approach represents a powerful tool in behavioral genetics and has been extensively reviewed elsewhere (46,47).
To increase the resources necessary for forward genetics strategies and to generate single-gene mutants displaying behavioral anomalies, several phenotype-based mutagenesis programs have been initiated. The review by Hunter et al. (48), in this issue, and Justice et al. (49) describe and list ongoing mutagenesis efforts in detail, so we discuss these efforts in the context of psychiatric genetics and behavioral genetic studies of targeted mutations. In addition, we provide an overview of critical issues in the identification of mouse models of psychiatric disorders, such as the definition of relevant phenotypes and the problems involved in characterization of novel behavioral mutants identified in random mutagenesis screens.
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‘GOOD GENETICS NEEDS GOOD PHENOTYPES’ (26) |
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TOPABSTRACTMOUSE MODELS FOR HUMAN...‘GOOD GENETICS NEEDS GOOD...IDENTIFICATION OF BEHAVIORAL...REFERENCES |
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The first priority in the search for behavioral mutants in the mouse is the identification and definition of phenotypes. A subset of the impressive collection of targeted mutants with behavioral phenotypes that have been reported in the last 2 years is listed in Table 1. A limitation of these studies has been the inability to directly compare these mutants and to correlate studies performed in different laboratories, primarily due to differences in experimental procedures and behavioral paradigms or the differing genetic backgrounds of these novel mutations. These concerns were recently confirmed by the observation that differing behavioral profiles have been observed in different laboratories, using the same inbred and mutant lines of mice and even after strictly controlling both environmental variables and experimental procedures (50). Although this finding was discouraging, the study by Crabbe et al. also had promising results in that the genetic variance was relatively high for all of the behaviors tested and large differences between strains were shown to be robust and unlikely to be influenced by specific laboratory environments (50).
Rather than providing a reason not to perform behavioral analysis, the study by Crabbe et al. provides guidelines regarding the variables that need to be addressed when doing behavior studies of any kind (50). For example, to address the problem of replication and uniformity of behavioral phenotyping, the analysis of novel behavioral mutants should be performed using a standard battery of tests which provide strong and consistent phenotypes. It has also been recommended that behavioral differences observed in mutant animals should be replicated in multiple laboratories and using multiple tests of a behavioral domain (50). This, of course, implies that behavioral mutants should be shared among investigators in the interest of confirming altered behaviors observed in their own laboratories. In addition, we suggest that behavioral assessment of one or two inbred strains (for example, C57BL/6 and DBA/2) should also be conducted along with wild-type littermates to provide a ‘running baseline’ by which to compare results at any given timepoint (51). This information will allow the calibration of behavioral or physiological parameters in novel mutations with those in the existing and generally available inbred strains, as well as provide a better basis for comparison of findings and experimental conditions from one laboratory to other. Finally, considerable thought should be given to controlling the genetic background on which the mutation is generated and maintained (52,53).
A major challenge in the analysis of rodent phenotypes is identification of those traits that correspond to endophenotypes in human disease. Based on recent studies, a number of relatively simple and robust behaviors have been selected as amenable to forward genetic approaches.
Sensorimotor gating
Deficiencies in attention and information processing have long been noted in patients with schizophrenia and other psychiatric illnesses (54,55). It is believed that the inability to filter out extraneous stimuli and process information that is presented in fairly rapid succession accounts for the tendency of schizophrenics to suffer from fragmentation of normal cognitive processes (56) and that these functions are vital to the maintenance of cognitive function (57). Some of these attentional deficiencies may be due to impairments in sensory gating (58). Sensory gating can be measured by the level of attenuation of a startle response (either acoustic or tactile) upon presentation of a non-startle-inducing prepulse stimulus (commonly called prepulse inhibition).
Prepulse inhibition of startle response (PPI) is one of the most easily transferred behavioral tests between humans and mice. In humans, the startle response can be measured as an eyeblink response or P50 event related potential suppression whereas in mice, it is generally measured as a whole-body response using commercially available startle chambers. Multiple studies have been conducted using inbred strains of mice to show that there is substantial genetic influence on both the startle response and PPI. In general, inbred strains vary in their response to both acoustic and tactile startle stimuli and display a wide range of variability in prepulse inhibition (51,59,60).
Several single-gene mutations show alterations in prepulse inhibition (Table 1). One example, in particular, shows the power of animal models to investigate possible candidate genes in human disorders. Prodh–/– mice, deficient for the gene that encodes proline dehydrogenase, show significantly lower levels of PPI in comparison with wild-type controls along with elevated levels of proline in the brain (20). Prodh is the mouse homolog of the Drosophila slgA (sluggish-A) gene. The human homolog lies on chromosome 22q11 in a region that has been associated with psychiatric illness and is, in some cases, deleted in psychiatric patients (61–63). In addition, elevated levels of proline have been reported in a patient with the 22q11 deletion (64).
Mice deficient for the neural cell adhesion molecule (NCAM-180) also display decreased PPI as well as increased lateral ventricle size (65). NCAM is involved in neural migration and a previous study has shown that it is markedly reduced in the hippocampus of schizophrenic brains (66). This study is particularly important because it lends evidence to the widely held belief that schizophrenia results from abnormalities in brain development (67,68).
Learning and memory
The use of rodent models to study the genetics of learning and memory began in the 1940s with the selective breeding of maze-dull and maze-bright rats (69). For several decades, much of the work in the genetic analysis of learning and memory consisted of basic behavior- or quantitative-genetic analysis using experimental models such as Drosophila and Phormia regina, the blowfly. However, the use of Mendelian crosses to perform genetic analysis was limited, only providing information about the genetic architecture of learning and memory and revealing that, in most cases, the genetics are complex and attributable to many genes. In the late 1960s, Seymour Benzer proposed the forward genetic approach of using chemical mutagens to disrupt single genes and screening lines of mutagenized flies to observe abnormal behaviors (70). Using this method, a multitude of genes for learning and memory have been identified in Drosophila (71).
There are several commonly used tasks to study learning and memory in mice. The hidden platform version of the Morris water maze is a test for spatial learning in which animals are trained to escape from a pool of water (72). Mice are given multiple training sessions to learn the placement of the platform using visual cues in the room. The platform is then removed and the search pattern of the animal is recorded. Animals that have learned the location of the platform will spend more time in the area that had previously contained the platform and will make more crosses over the platform site. Different configurations of the water maze measure different forms of learning and utilize different brain systems. A second commonly used paradigm for studying learning and memory is the conditioned fear test. The direct measure of freezing behavior in response to discrete conditioned stimuli such as tones or lights as a measure of learning was first conducted by Bouton and Bolles (73). Fear conditioning can evaluate two discrete forms of learning, cued and contextual, and there is evidence that different neural substrates support these two forms of learning (74).
Genetic manipulations, including gene targeting, are being utilized extensively to test the role of genes in learning and memory (Table 1) (41,42). These studies were initiated with genes or proteins shown previously by pharmacological studies to be involved in synaptic plasticity. For example, null mutations in the 
calcium calmodulin kinase II (75,76), CREB (77,78), PKC
(79,80), NMDA receptor 
1 subunit (81), adenylate cyclase (82,83) and mGluR5 (84) revealed anomalies in different forms of synaptic plasticity and in learning and memory. The relationship between long-term potentiation (LTP) and behavioral affects on learning and memory are particularly intriguing in recently generated hypermorphic and conditional mutants. For example, it was reported that mice overexpressing the NMDA receptor 2B (Grin2b) in the forebrain show enhanced learning and memory in a variety of behavioral tasks including the Morris water maze, conditioned fear, novel-object recognition and fear extinction and also exhibit enhanced LTP, thought to underlie some forms of learning and memory (85). Deficits in learning and memory are apparent in conditional knockouts for the neurotrophin tyrosine kinase receptor (TrkB) (43). Trkb conditional knockout mice (the knockout is restricted to the forebrain and occurs only during postnatal development) do not learn the Morris water maze, perform poorly in the radial maze task and show reduced LTP in the hippocampus (43). Despite these recent examples linking LTP and learning, there is also growing evidence of dissociation between the two (86–88). In a more recent example, mutant mice lacking the L--amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunit GluR-A (GluR-A–/–) showed an absence of LTP in the hippocampus, but exhibited no deficits in spatial learning (89).
A significant outcome of studies described above is that many of the same biochemical components and common molecular mechanisms underlie learning and memory in invertebrate and vertebrate systems (for a review see ref. 41). Systematic assessment of learning and memory in targeted mutations, as well as in mutants from random mutagenesis screens, will reveal differences between these pathways, and facilitate identification of genetic components that are specific for a mammalian system, including factors that are involved in human disease.
Anxiety
The manifestation of anxiety in a number of psychiatric disorders, including panic disorder, generalized anxiety disorder, specific and social phobias, obsessive-compulsive disorder, depression and post-traumatic stress disorder, highlights the importance of gaining a better understanding of its genetic etiology.
The use of animal models to study anxiety-related behaviors has a long history (90,91). The most commonly used assay for testing anxiety in both rats and mice has historically been the brightly lit open field (90). Other assays have also been developed and are now widely used, including the elevated plus maze (92,93) or zero maze (94). Both tests take advantage of the fact that rodents are fearful of bright and/or open spaces yet also have a tendency to explore novel environments. All of the tests allow measurement of a variety of ‘anxious’ or ‘non-anxious’ behaviors including time spent in closed or dark areas versus open or lighted areas, wall-seeking tendency (thigmotaxis), defecation and exploratory activity. The hallmark of a relevant animal assay for anxiety is, of course, the ability of either anxiolytics or anxiogenics to reverse an animal’s behavior on the test and many of the paradigms listed above were developed to study the efficacy of various anxiolytic drugs. The validation of relating rodent anxiety to human anxiety has been proven numerous times using these behaviors (95–97).
There are numerous examples of mice with null mutations in a variety of genes which express abnormal behavior in several different assays for anxiety (Table 1). Some of the more notable examples include the serotonin gene knockouts, Htr1a and Htr1b, that have been tested by multiple groups and have consistently shown elevated (Htr1a) or reduced (Htr1b) anxiety (98–103). In addition, three different studies have investigated anxiety-related behaviors in knockouts for the corticotropin-releasing hormone (Crhr1) gene (104–106) and all three studies showed reduced anxiety in the null mutants. The consensus in behaviors observed between the different laboratories in both the serotonin and Crhr knockouts validates the conclusion by Crabbe et al. (50) that differences seen in genetically engineered mice cannot stand on their own until they are replicated and validated in different behavioral paradigms and across different laboratories.
Sleep and circadian rhythms
Deficits in sleep and circadian rhythms are part of the symptomatology of a variety of psychiatric disorders including bipolar disorder and depression. The earliest understanding of the genetic nature of circadian rhythms came from the identification of circadian mutations in Drosophila (period) (107) and Neurospora (frequency) (108). Genetic studies identified additional genes in the circadian system and their gene interactions provide one of the best characterized and evolutionarily conserved molecular genetic pathways underlying behavior (for a review see ref. 109).
Single-gene mutations in the mouse have played an important role in the dissection of the circadian pathway. Several years ago, the identification of the Clock gene, starting with an ENU-induced mutation, provided the first transcription factor in the circadian feedback loop (110,111). Recently, null mutations for other components of the clock have been generated. Mutants lacking the Period2 gene (mPer2), one among three known homologs of the Drosophila period (per) gene, display a shorter circadian period and loss of circadian rhythmicity in total darkness (112). Studies in Arabidopsis thaliana identified cryptochromes, blue light receptors (113). Targeted null mutations for the mouse homologs (Cry1 and Cry2) showed that these genes are essential for the maintenance of circadian rhythmicity rather than entrainment to light cues (114–116). Cryptochrome 1 knockouts (Cry1–/–) have a shortened circadian period of ~1 h (114,116) while Cryptochrome 2 (Cry2) knockouts have a lengthened circadian period of ~1 h (114,115). In total darkness, double knockouts of Cry1 and Cry2 (Cry1–/–/Cry2–/–) display complete arrythmicity, indicating that they no longer have any internal circadian clock, and that the two genes have partially overlapping function (114,116).
A fascinating finding in the field of genetics of sleep was reported last year when it was discovered that a null mutation in the orexin (also known as hypocretin, Hcrt) gene resulted in narcolepsy-like behavior and changes in the electroencephalographic (EEG) pattern in mice (117). Furthermore, it was also reported that modafinil, an anti-narcoleptic drug, activates orexin-containing neurons. This finding, in conjunction with the behavioral and EEG observations, led the authors to conclude that these knockout mice are a model for human narcolepsy. Another landmark discovery is the identification of the orexin receptor 2 as the gene disrupted in the dog model of narcolepsy (118). In general, these studies represent a powerful example of the marriage of reverse and forward genetic approaches in the identification of components of an important neurobiological and physiological pathway.
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IDENTIFICATION OF BEHAVIORAL MUTANTS IN PHENOTYPE-BASED MUTAGENESIS SCREENS |
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TOPABSTRACTMOUSE MODELS FOR HUMAN...‘GOOD GENETICS NEEDS GOOD...IDENTIFICATION OF BEHAVIORAL...REFERENCES |
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Recently, a number of random and chromosomal region-specific mutagenesis programs have been initiated to take advantage of the power of single-gene mutations for developing an understanding of complex disorders. Many of these efforts are focusing on a wide range of phenotypes including physiological assays and developmental phenotypes, as well as neurological and behavioral traits (49,119–121). In this section we discuss insights into the nature of behavioral anomalies that can be drawn from studies of mice with targeted mutations in known genes, and consideration of these issues in designing a random mutagenesis screen.
Ongoing mutagenesis efforts have already identified an array of novel mutants (http://www.mgu.har.mrc.ac.uk/mutabase/ ; http://www.gsf.de/isg/groups/enu-mouse.html ; http://www.montana.edu/wwwmri/enump.html ), including those with behavioral phenotypes. Novel mutants with anomalies in circadian behavior, rest–activity patterns, sensorimotor gating, anxiety and learning and memory have been reported and phenotypic characterization and genetic mapping of these mutations is in progress (as reported at the 13th International Mouse Genome Conference in Philadelphia, PA, and the Mouse Molecular Genetics meeting in Heidelberg, Germany). Characterization of these mutations may take a course that will differ from characterization of mutations with visible phenotypes or more obvious neurological symptoms. Some caution, persistence and patience will be necessary in the search for mutations based exclusively on abnormal behavioral phenotypes, as well as in identification of the genes defined by these loci. In general, reduced penetrance, variable expressivity and sensitivity to genetic background, as well as the influences of environmental factors, hamper the characterization of mutants identified in random mutagenesis screens. The Clock mutation represents the only published behavioral mutation identified in a random mutagenesis screen. Future studies will show how many behavioral mutants will have as robust a phenotype as Clock.
Although the identification and cloning of the Clock mutation illustrated the value and efficacy of a dominant screen, it is important to broaden and extend screens to those that have the potential of uncovering recessive mutations. With a dominant screen, a large number of genes may be missed. For example, among targeted behavioral mutants, only a small number of lines show dominant or semidominant phenotypes (43,122). Future studies will show whether this can be attributed to the fact that the majority of genes do not have abnormal phenotypes when present in one copy, or whether mutations with dominant behavioral phenotypes are indeed rare. Sophisticated electrophysiological, neuropathological or neurobiochemical assessments of novel mutations may uncover subtle anomalies in heterozygotes that would be missed by routine behavioral observation. This point can be illustrated with the recently reported Trkb conditional knockouts (43). Whereas in homozygotes, impaired LTP of hippocampal synapses is accompanied by impaired learning, in heterozygotes, a partial reduction of LTP can be detected, but no apparent behavioral anomalies have been observed in currently utilized learning and memory tasks. This suggests that the presence or absence of a dominant phenotype is not an absolute finding and may depend on how hard one looks for this phenotype.
Another important question that remains is how many dominant behavioral mutations will be associated with developmental or visible anomalies in homozygotes or, conversely, how many embryonic lethal mutations will have dominant behavioral phenotypes. From a human genetics standpoint this is an important question, because genes with a role in development could also be considered as candidate genes for susceptibility to psychiatric disorders. For example, mutations in Presenilin 1 (Pre1) cause early-onset familial Alzheimer’s disease (123). A targeted null-mutation in this gene in mice is associated with embryonic lethality due to defects in somite segmentation (124). It will be interesting to examine the behavior or neuropathology of Pre1–/+ heterozygotes or await behavioral analysis of mice with the spectrum of point mutations seen in human Alzheimer’s disease.
Over the last years, the field of targeted mutagenesis has provided several examples of mutations with strong phenotypes when combined with other mutations, although the single gene mutations did not exhibit any anomalies or, at the least, weak phenotypes (114,125,126). These findings provide an important clue in the search for novel behavioral mutants using random mutagenesis. Mutations with phenotypes that are weak or show incomplete penetrance may be tested in combination (double mutant analysis) with other available mutants. Moreover, random mutagenesis screens for novel phenotypes in existing mutations generated by targeted mutagenesis (so called ‘sensitized screens’) may be particularly useful in the identification of genes in the same molecular or genetic pathway. The use of sensitized screens for behavioral phenotypes that combine random mutagenesis with pharmacological manipulations may yield mutations that affect a defined neurochemical pathway.
A mutagenesis screen currently being performed in our laboratory involves examination of G1 progeny of ENU treated mice in a battery of behavioral paradigms, such as the zero maze, rotarod, acoustic startle response, olfaction and analysis of wheel running activity patterns under light:dark and constant dark conditions (L. Tarantino, S. Kanes, J. Schimenti and M. Bucan, unpublished data). This experimental paradigm allows us to evaluate, prior to testing inheritance, how specific or pleiotropic the behavioral anomalies are in identified phenotypic deviants. Whereas mutants with specific phenotypes may be of particular value, combinations of phenotypes in single-gene mutations may be even more informative in the search for models of psychiatric disorders. Epidemiological evidence indicates that comorbidity may be the rule rather than the exception in behavioral disorders in humans. For example, the co-occurrence of anxiety disorders, substance abuse and recurrent unipolar disorder has been documented repeatedly (127,128). Therefore, single-gene mutants in the mouse, generated by either forward or reverse genetic experiments, should be examined for a variety of phenotypic traits. Combinations of phenotypes which are found together in a human syndrome will be of particular importance.
The impending elucidation of the complete sequence of both the mouse and human genomes along with the ability to perform expression profiling of a large number of genes to compare mutant and wild-type animals, will increase the value of generated mutations, facilitate positional cloning of the mutant gene and aid in the understanding of the molecular pathways affected by these mutations.
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ACKNOWLEDGEMENTS |
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The authors would like to thank their colleagues in the Center for Neurobiology and Behavior for numerous discussions, and Drs Ted Abel, Wade Berrettini, Margit Burmeister, Thomas Gould, Steve Kanes, Robert Lenox and Dani Reed for comments on this manuscript. This research is supported by NIH grants MH57855 (M.B.), AR45325–02 (M.B.). L.T. was partially supported by NIMH Training Grant MH19112.
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FOOTNOTES |
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+ Present address: Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, San Diego, CA 92121, USA
§ To whom correspondence should be addressed. Tel: +1 215 898 0020; Fax: +1 215 573 2041; Email: bucan@pobox.upenn.edu
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