22 | MOUSE MODELS OF SCHIZOPHRENIA AND BIPOLAR DISORDER

MIKHAIL V. PLETNIKOV AND CHRISTOPHER A. ROSS

INTRODUCTION

Animal models are experimental systems that are developed to study particular aspects of a disease, as no model can accurately reflect all features of the disease. Modeling of human neuropsychiatric disorders in animals is especially challenging (Nestler and Hyman, 2010).

An example of both the opportunities and difficulties of mouse model research is seen with Huntington’s disease (HD). HD is a single gene disorder whose genetics and neurobiology are relatively well understood (Ross and Tabrizi, 2011). The clinical symptoms of human HD include patho­gnomonic involuntary and voluntary movement disorders, cognitive decline, and emotional changes, with inexorable progression to death. These are accompanied by selective neuronal degeneration in the striatum and other brain regions. The disease is caused by a single mutation, a CAG repeat expansion at the Huntingtin locus. There have been over a dozen attempts to model this disease in mice (Crook and Housman, 2011). These models had some outstanding successes. For instance, the characteristic intranuclear inclusions containing aggregated Huntingtin protein were first discovered in the mouse model, and this discovery enabled their identification in humans. The mice generally do have some motor and cognitive abnormalities, and in some cases there is a progressive phenotype ending in early death. However, most of the models do not have the massive striatal neurodegeneration seen in the human disease. Most of the models do not have the involuntary movement disorder. Many of the models have weight gain instead of the progressive weight loss seen in most HD cases. Thus, it is important to keep in mind that even in a disorder that should be relatively straightforward, the mouse models have both strengths and weaknesses, and demand careful and cautious interpretation.

During the last three decades multiple animal models of schizophrenia and bipolar disorder have been generated, based on environmental exposures, drug-induced behaviors, or lesions. We might categorize different kinds of animal models in terms of their relationship to the cognate human diseases.

Phenotypic models attempt to model aspects of the phenotype of the disease, often picking behaviors that are reliably measured in animals, such as motor activity, acoustic startle responses, or various kinds of learning. These may or may not reproduce the pathophysiology of the human disorder, but may be useful for pharmacology.

Pathophysiological models attempt to mimic some key aspect of the biology, though not necessarily the etiology of the human disorders. For instance, since abnormal neurodevelopment is increasingly seen as central to schizophrenia, ­perturbations of brain development (Lu, 2011) may model some aspects of the biology of the disorder. It is important to interpret developmental mouse models in the context of emerging knowledge of the circuitry of psychiatric disorders (Lewis and Sweet, 2009; Ross et al., 2006), including cortical and subcortical circuits. Much attention has been given to modeling alterations in dopamine signaling; however this may be more relevant to antipsychotic pharmacology than to human disease pathogenesis.

Finally, etiologic models have the potential to match most closely the human disorders. Presumably, the pathophysiology should also be congruent if the etiology is congruent. Etiologic models could be either environmental or genetic. However, while environmental factors, including pharmacologic exposure, clearly contribute to psychiatric disorders, the exact factors and their time course, are not yet well defined, and so it is difficult to model them. Therefore, taking into account the strong evidence for genetic contributions to the development of schizophrenia and bipolar disorder, genetic models may be the most specific way to attempt to match the human neurobiology, and hopefully model pathogenesis and, ideally, response to treatment.

In this review we will mention some of the non-genetic models, but focus on genetic mouse models, evaluate their advantages and limitations, and comment on potential new prospects for the field. We will focus on single gene alterations and attempts to model copy number variation. For most genetic contributors to human psychiatric disorder, the pathophysiologic mechanisms are poorly understood. For instance, genetic variation could lead to overall loss of function, gain of function, misregulation of gene expression and function, or other more complex changes. Until specific causative mutations are identified, models will have to depend on hypotheses about gain or loss of function or other alterations.

NON-GENETIC MODELS

PHARMACOLOGICAL MODELS

One approach to animal models of schizophrenia and bipolar disorders is based on use of pharmacological challenges. These models are mainly relatively acute phenotypic models, though exposure to psychostimulants, cannabis, PCP, and other drugs may contribute to susceptibility to human psychiatric disorders. In addition, these pharmacologic models may be able to mimic the behavioral effects of treatments used in clinic (pharmacological isomorphism) and to predict pharmacological effects of experimental compounds to become future therapeutics (predictive validity) (Matthysse, 1986).

Among pharmacological animal models of schizophrenia, phencyclidine (PCP)- or amphetamine-induced hyperactivity are most popular. Similarly, amphetamine-induced hyperactivity has been widely used to model mania (Berggren et al., 1978; Davies et al., 1974; Gould et al., 2001; Kato et al., 2007), although lithium does not seem to attenuate amphetamine-induced changes in healthy volunteers (Silverstone, 1998). The major caveat of drug-induced hyperactivity models is that hyperactivity is one of a broad set of symptoms of several psychiatric diseases, including schizophrenia, attention-deficit hyperactivity disorder, and bipolar disorder (Young, 2011). Since pharmacological treatments of schizophrenia and bipolar disorder are largely symptom-based or palliative, animal models that mimic behavioral responses to drugs are less likely to provide insights into the pathogenic mechanisms of disease and more likely to illuminate behavior pharmacology (Elenbroek and Cools, 1995).

BEHAVIORAL OR SYMPTOM-ORIENTED MODELS

Another approach to animal models of schizophrenia and bipolar disorder mimics behavioral abnormalities of the disease. Critically, in addition to evaluation of how accurate modeled animal behaviors reflect human symptoms, animal models of face validity are also scrutinized in pharmacological studies to evaluate if an altered behavior is responsive to treatments also used in clinical settings. For example, disrupted prepulse inhibition (PPI) of the acoustic startle and abnormal social interaction mimic impaired sensorimotor gating and social withdrawal observed in schizophrenia patients and can be improved by typical and atypical antipsychotics). Symptoms of mania that can be modeled in animals include increased activity, irritability, reduced need for sleep (or other changes in sleep patterns), aggressive behavior, sexual drive, distractibility, and risk-taking behavior, all of which are commonly observed in human mania (Einat, 2006). Models of the depressive phase of bipolar disorder usually utilize models validated in the context of depression research (see the chapter on models of depression), such as models of anhedonia, sleep disorder, poor hygiene, and changes in appetite or weight (Cryan and Holmes, 2005).

However, key positive and negative symptoms of schizophrenia or mood swings in bipolar disorder cannot be fully reproduced in animals. Even when schizophrenia-like alterations such as hyperactivity or social behavior deficit are modeled, it is unclear whether they arise from the same pathological processes, since hyperactivity can be induced by a great variety of drugs and manipulations irrelevant to the etiology and neuropathology of schizophrenia or bipolar disorder (Ridley and Baker, 1982).

PATHOGENIC NON-GENETIC MODELS

An additional approach to animal models involves attempts to reproduce pathogenic processes underlying the disease. These models are based on the concept that behavioral deficits in humans are due to disturbances in the brain functioning that could be modeled in animals (Elenbroek, 1995). Abnormal neurodevelopment is believed to be an important factor leading to behavioral deficits (Jaaro-Peled et al., 2010). Thus, animal models of abnormal brain and behavior development are likely to be most informative for our understanding of the neurobiology of schizophrenia and bipolar disorder (Insel, 2010; Kamiya et al., 2012).

During the last three decades several animal models of schizophrenia have been generated based on environmental exposures and lesions in developing and adult rodents (Lipska and Weinberger, 1993, 1995). The similar approaches have been utilized for neurodevelopmental models of bipolar disorder. For example, the exposure of the animals to early social isolation or early postnatal lesions in amygdala may produce the symptoms resembling aspects of mania, such as increased locomotor activity and enhanced sensitivity to the locomotor-activating effects of amphetamine (Swerdlow, 2001). In the context of recent reports on using transcranial magnetic stimulation as a treatment for depression, use of electrically or chemically induced kindling to study the development of new episodes in bipolar disorder is also of an interest (Kalynchuk, 2000). Still, all these non-genetic pathogenic animal models do not really address the etiology of the diseases and will unlikely advance uncovering new therapeutic targets.

GENETIC MOUSE MODELS OF SCHIZOPHRENIA

Genetic models have the potential to model both etiology and pathogenesis. Recent genetic studies are finally yielding replicable genetic loci for the human disorder. Most mouse work to date has relied on genes identified in linkage studies, which may contribute risk in small families though not necessarily in the entire population. However in other disorders, genes identified in small families have often turned out later to be relevant to the population at large. Since psychiatric genetics is still in a relatively early stage, it is difficult now to know which genes will confer the greatest amount of risk in different populations. Furthermore, alterations of genes whose gene products are involved in pathogenic pathways may be very useful even if the gene altered does not turn out to contribute a large amount of risk in human populations. In the future, likely more models will be available from loci confirmed in large GWAS or sequencing studies. For now, much of the work is on genes identified in smaller studies.

MODELS BASED ON GENES FROM ­ GENOME-WIDE ASSOCIATION STUDIES

Most of the candidate genes studied to date emerged from relatively small linkage or association studies, and have not been seen in genome-wide association studies, so their relevance to schizophrenia in the population is uncertain (Sklar et al., 2008). Genome-wide association studies offer an unbiased assessment of variation across the entire genome, with the ability to identify specific disease variants (Bergen et al., 2012; Lee et al., 2012). A recent list of the risk genes associated with schizophrenia at genome-wide significance level includes zinc finger binding protein 804A (ZNF804A), the major histocompatibility (MHC) region on chromosome 6, neurogranin (NRGN), and transcription factor 4 (TCF4) (e.g., Lee et al., 2012). In addition, Ripke and colleagues have identified the microRNA MIR137 and its targets (Ripke et al., 2011). Generating animal models with the risk variants and characterizing molecular, cellular, behavioral, and other processes will help to link these genes to disease mechanisms. However, animal model research in this field is only starting. Here, we review a few experimental studies available in the literature to date (fall of 2012).

MHC

The most replicated schizophrenia GWAS association is the MHC locus, though multiple genes involved in immunity, neurodevelopment, synaptic plasticity, and other processes present a challenge for linking specific genes in this region to pathophysiology (Corriveau et al., 1998; Huh et al., 2000;). Many MHC mouse studies focus on species-specific recognition as a part of mating behavior (Hurst, 2009). A few investigations have been performed to address roles for this locus in other behaviors. For example, it has been reported that mice deficient for both H2-K(b) and H2-D(b)(K(b)D(b-/-)) have a lower threshold for induction of long-term depression (LTD) at parallel fiber to Purkinje cells synapses and improvement in acquisition and retention of a Rotarod behavioral task. These results suggest a role for classical MHCI molecules in synaptic plasticity and motor learning (McConnell et al., 2009). Unlike wild-type animals, mice lacking both β-2-microglobulin and transporter associated with antigen processing (β2M-/-TAP-/-) showed a greater hypothalamic pituitary adrenal activation to saline injection, while lipopolysaccharide-induced cytokine expression in the hypothalamus was similar in β2M-/-TAP-/- and wild type mice, suggesting that class I MHC plays a role in stress reactivity (Sankar et al., 2012).

An interesting approach to the behavioral effects of the MHC locus is to compare behaviors between MHC-congenic strains of mice or rats, which are genetically identical to each other except for the locus. Spatial learning and memory in male and female mice of two MHC-congenic strains (C57BL/6J and B6-H-2K) in two versions of the Hebb-Williams maze were evaluated. In the food-reward paradigm, males required fewer sessions to learn than females, but there were no strain differences in acquisition. The B6-H-2K mice reached the goal box faster than the C57BL/6J mice. In the water-escape paradigm, the C57BL/6J mice required more sessions than the B6-H-2K mice during acquisition. Thus, these two strains are comparable in cognitive ability but still show differences in performance in the Hebb-Williams maze (Stanford et al., 2003).

TCF4

A putative role of the basic helix-loop-helix (bHLH) transcription factor TCF4 in the adult brain has been evaluated in transgenic mice that moderately overexpress TCF4 in the postnatal brain. TCF4 transgenic mice display profound deficits in contextual and cue-dependent fear conditioning and sensorimotor gating. Molecular analyses revealed the dynamic circadian deregulation of neuronal bHLH factors in the adult hippocampus. This study describes the first animal model relating to TCF4, and suggests that this transcriptional factor contributes to cognitive processing (Brzózka et al., 2010).

MODELS BASED ON COPY NUMBER VARIATION

Recent studies have implicated structural variations in the genome (copy number variations) in schizophrenia (Malhotra and Sebat, 2012). A 22q11 deletion has long been known to lead to 25-fold increase in the risk for schizophrenia (Murphy et al., 1999), though it is uncertain to what extent this corresponds to other forms of the disease. 22q11.2 deletion syndrome, DiGeorge syndrome (DGS), or velo-cardio-facial syndrome (VCFS) is associated with craniofacial and cardiovascular abnormalities, immunodeficiency, hypocalcemia, short stature, and cognitive dysfunctions (Karayiorgou et al., 2010). The orthologous region of the human 22q11.2 locus is located on mouse chromosome 16 with a high degree of conservation within the 22q11.2 region (Drew, 2011). Both long-range deletion models and single gene knockout (KO) preparations have been described. Here, we only briefly review mouse models related to the deletion. Comprehensive recent reviews of this topic are available elsewhere (e.g., Karayiorgou et al., 2010).

Two of the long-range deletion models—the Df(16)A-/-model (Stark, 2008) and the LgDel/- model (Merscher et al., 2001)—lack the entire 1.5 Mb region on one chromosome, most closely modeling the human 22q11.2 deletion. These models have been reported to display impaired working memory and prepulse inhibition (PPI) of the acoustic startle, similar to the phenotypes of individuals with the 22q11.2 deletion syndrome (Paylor, 2006; Stark, 2008).

Among single gene KO mouse models involving the region of the deletion, PRODH is a promising candidate gene (Li, 2008) that encodes a mitochondrial enzyme to metabolize L-proline, a putative neuromodulator of Glu and GABA neurotransmission. Genetic variants in this gene have been associated with hyperprolinemia type 1 and schizophrenia (Harrison and Weinberger, 2005). Mutant mice with reduced PRODH enzymatic activity show abnormal associative conditioning (Gogos et al., 1999; Paterlini et al., 2005). These mutant mice were reported to have increased levels of COMT, possibly as a compensation for enhanced DA signaling in prefrontal cortex (PFC). Blockade of COMT in PRODH KO mice impairs learning in T-maze task (Paterlini et al., 2005). These results suggest an epistatic interaction between COMT and PRODH (Kvajo et al., 2011), consistent with a similar interaction reported for patients with 22q11.2 deletion (Raux, 2007). A growing appreciation of the fact that a large number of schizophrenia cases result from copy number variations provides the good rationale for the development of models based on chromosomal engineering and other advanced techniques to manipulate sizable segments of DNA (Nomura and Takumi, 2012).

MODELS BASED ON GENES FROM LINKAGE STUDIES

Genetic models of candidate genes emerging from early linkage studies have been also generated, including dysbindin, neuregulin 1, and Disrupted-in-Schziophrenia-1 (DISC1), which have attracted the most attention and are described here in greater detail. It is notable that most candidate genes that have been studied to date have not been well supported by GWAS studies (Collins et al., 2012). These include COMT, dopamine receptors, neuregulin, dystrophin, BDNF, and other genes. It is possible that genes that do not have a signal in GWAS studies may still be important in familial or other subtypes of the disorder.

DYSBINDIN

Dystrobrevin-binding protein 1, or dysbindin, encoded by the DTNBP1 gene and discovered through screening for binding partners of α-dystrobrevin (Benson et al., 2001) is a part of the dystrophin-associated protein complex (DPC) and of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) (Nazarian et al., 2006). The dysbindin locus was first identified in an Irish study (Straub et al., 2002), and some research has supported relevance of this gene to schizophrenia, including haplotypes of the gene linked to the negative symptoms, or cognitive functioning in healthy people (Talbot, 2009). Postmortem studies also found reduced expression of the gene and protein in the hippocampus and PFC (Talbot, 2009; Weickert, 2008), where decreased expression of the protein can affect synaptic neurotransmission (Iizuka et al., 2007) and synaptic stability.

The role for dysbindin in vivo has been mainly evaluated using mice with spontaneous deletion in the Dtnbp1gene, leading to loss of dysbindin in “sandy” mice of DBA/2J strain (Li et al., 2003; Talbot, 2009). Sandy mice model type VII Hermansky-Pudlak syndrome, which is characterized by oculocutaneous albinism, prolonged bleeding, and pulmonary fibrosis. Earlier studies suggested that dysbindin can be involved in regulation of exocytosis and vesicle biogenesis in neurons and detected diminished levels of snapin (a SNAP25-binding protein) in sandy mice that may partially explain alteration in neurotransmission and behaviors (Chen et al., 2008; Feng et al., 2008). Nagai et al. (2010) observed decreased KCl-evoked DA release in prefrontal cortex, in line with attenuated behavioral sensitization after repeated methamphetamine. In addition, lower expression of dysbindin was associated with decreased NMDA-evoked currents in PFC neurons and decreased NR1 expression that correlated with spatial working memory performance (Karlsgodt et al., 2011). Parvalbumin (PV)-positive neurons were reported to be affected in these mutant mice as well, including impaired inhibition and decreased PV cell immunoreactivity, suggesting a link between this candidate gene and the auditory endophenotypes (Carlson et al., 2011).These endophenotypic studies were further extended in a recent MRI analysis that found the structural volume deficits in cortical regions, subiculum and dentate gyrus, and the striatum were found in mutant mice (Lutkenhoff et al., 2012).

The molecular and neuronal abnormalities in sandy mice may underlie the behavioral phenotypes, including deficits in social interaction, long-term memory, novel object recognition, and working memory (Feng et al., 2008; Jentsch et al., 2009). Moreover, the most recent reports have described interaction of dysbindin with another candidate gene, Disrupted-in-Schizophrenia-1 (DISC1), suggesting overlapping intracellular signaling pathways for these two important proteins (Camargo et al., 2007; Ottis et al., 2011).

NEUREGULIN 1

Neuregulin 1 (NRG1) and its receptors, ErbB2 and ErbB4, appeared in linkage studies (Stefansson et al., 2002), though again, not yet in genome-wide association studies. Thus, while there has been a large amount of interesting neurobiology brought forward to date, it is not yet clear how relevant it will be to human disease.

Neuregulin-1, also known as heregulin, acetylcholine receptor inducing activity (ARIA), glial growth factor (GGF), or sensory and motor neuron derived factor (SMDF), is encoded by the NRG1 gene located on chromosome 8p13 (Law et al., 2006). Chromosome 8p, mainly the region around 8p21.1–22, has been implicated as a locus harboring one or more susceptibility genes by several linkage studies (Goes FS et al., 2008). Association of this gene with schizophrenia has been replicated, although some contradictions exist (Chen et al., 2006; Harrison and Law, 2006). The SNPs associated with schizophrenia were positioned either before exon 1 or in the introns, and no functional mutations have been identified (Gogos et al., 1999; Mei and Xiong, 2008). Polymorphisms in the intronic regions of this gene are associated with variation in cognitive functions in healthy individuals (Silberberg, 2006; Roussos et al., 2012) and may alter NRG1 expression. Both upregulation and downregulation in expression of mRNA or protein in postmortem brain samples have been reported (Hashimoto et al., 2004; Law et al., 2006; Chong et al., 2008).

NRG1 has been implicated in neuronal migration, synaptogenesis, gliogenesis, neuron-glia interplay, myelin formation, and synaptic neurotransmission (Harrison, 2006). Recently, one of the NRG-1 isoforms has been found to be predominantly expressed prenatally, suggesting a role in neurodevelopment (Tan, 2007). Alternative splicing of NRG1 results in at least 15 isoforms that all contain an extracellular epidermal growth factor (EGF)-like domain, which is sufficient for NRG1 biological activity, and the transmembrane (TM) domain that is common to most NRG1 isoforms (Mei, 2008). Deletion of Nrg1 and its receptor, ErbB4, are lethal, and mice die before birth (Meyer and Birchmeier, 1995). Thus, most studies have been performed using either heterozygous mice or Nrg1 hypomorphic mice that have mutations in the different domains of the gene.

Meyer and Birchmeier generated mice with targeted deletion of the EGF-like domain (NRG1-EGF+/-) by fusing exon 6 of the neuregulin gene to β-galactosidase, which results in partial deletion of the EGF-like domain of all three major types of Nrg1 (Meyer and Birchmeier, 1995). These mice exhibited elevated activity in open field, improved rotorod performance, and a better performance in T-maze spontaneous alternation task that may be explained by hyperactivity (Gerlai et al., 2000) that can be partially reversed with clozapine (Stefansson et al., 2002). Nrg1 mutant mice also exhibit improved habituation to a new environment, and impairment in PPI after pharmacological challenge with psychostimulants (Duffy et al., 2008).

An NRG-1 KO mouse model that lacks the transmembrane domain was also generated. Heterozygous (HET) mice have no gross alterations in the appearance but display increased activity and deficient PPI reversible by clozapine (Karl, 2007). Mice have no abnormalities in spatial learning but are aggressive (O’Tuathaigh et al., 2007). Compared to wild-type mice, Nrg1+/− mice display increased locomotor activity at 12–16 weeks of age, but not at 6 months. John Waddington and his associates evaluated Nrg1 “knockouts” for four topographies of orofacial movement, both spontaneously and under challenge with the D(1)-like dopamine receptor agonist, SKF 83959. They report that mutants exhibit increased spontaneous and induced incisor chattering, vertical jaw movements, and tongue protrusions. The level of horizontal jaw movements was elevated, while that of tongue protrusions was decreased in mutants, suggesting that Nrg1 may be involved in the regulation of orofacial dyskinesia (Tomiyama, 2012). Deletion of Nrg1 also leads to reduced thermal pain but does not alter the antinociceptive effects of tetrahydrocannabinol (THC) (Walsh, 2010). Another behavioral pharmacology study assessed the effects of MK-801 and phencylclidine (PCP) in these mice. Nrg1 male mutants display attenuated responses to the effects of acute PCP, while subchronic treatment with MK-801 and PCP comparably affect social behaviors in WT and KO mice. The total ventricular and olfactory bulb volumes were found decreased in mutants, but there were no group differences in levels of N-acetylaspartate, glutamate, or GABA (O’Tuathaigh et al., 2010).

The behavior of mice heterozygous for a mutation in neuregulin-1’s immunoglobulin (Ig)-like domain (Ig-Nrg-1 mice) was also assessed. These mutants demonstrate clozapine suppression of open-field and running wheel activity and impaired latent inhibition. Unlike other Nrg-1 mutants, Ig-Nrg-1 mice are not hyperactive, suggesting a distinct contribution of this domain to behavioral phenotypes (Rimer et al., 2005). The relatively mild phenotypes of Nrg1 HET mutants might be a result of functional compensation by Nrg2 and/or Nrg3.

A loss-of-function mouse model for type III Nrg1 was also generated. Type III NRG1 is transcribed by a different promoter and is expressed in mPFC, ventral hippocampus, and ventral subiculum. Adult type III Nrg1 HET mice have enlarged lateral ventricles and decreased dendritic spine density on pyramidal neurons. These brain abnormalities were associated with impaired spatial alternation and PPI rescued by chronic nicotine treatment. This model demonstrates a role of type III Nrg1 signaling in the neural circuits involved in sensorimotor gating and short-term memory (Chen et al., 2008).

Several studies evaluated the effects of increased Nrg1 expression using transgenic approaches. Overexpressing Nrg1 in all tissues increased locomotor activity, decreased fear conditioning, and abnormal social behaviors (Kato et al., 2010). Transgenic Nrg1 mice were found to have more parvalbumin-positive neurons and elevated levels of myelination markers in PFC (Kato et al., 2010).

NRG1 acts by stimulating a family of single-transmembrane receptor tyrosine kinases called ErbB proteins (Mei and Xiong, 2008). ErbB proteins have homology with the EGF receptor (EGFR, also known as ErbB1). ErbB4 is the only autonomous NRG1-specific ErbB that can both interact with the ligand and become activated by it as a tyrosine kinase. NRG1 signaling is mediated by heterodimers of ErbB2–ErbB3, ErbB2–ErbB4 and ErbB3–ErbB4 and by the homodimer ErbB4–ErbB4. Consistently, ErbB2 and ErbB3 mutant mice, whose strain origin was identical to that of heregulin mutants, showed no sign of the behavioral alterations (Gerlai et al., 2000). In contrast, ErbB4 heterozygous mice are hyperactive (Stefansson et al., 2002).

In order to study the role for the Nrg1 receptor in progenitor cells, a conditional KO model was generated using mice that express Cre under the nestin promoter. KO mice survived into adulthood and showed no behavioral deficits in locomotion. KO mice also display reduced grip strength compared to WT mice, while HET mice showed an intermediate phenotype. However, HET KO showed abnormalities in Morris water maze learning and memory task relative to WT (Golub et al., 2004).

Selective deletion of ErbB4 in PV-positive neurons prevented NRG1 from promoting activity-dependent GABA release to inhibit the activity of pyramidal neurons. These mutant mice showed hyperactivity, impaired contextual and working memory, and disrupted PPI. Some of these phenotypes were ameliorated by acute treatment with a low dose of diazepam, consistent with impaired GABA neurotransmission. These results indicate that NRG1 regulates the activity of pyramidal neurons by promoting GABA release from PV-positive interneurons, identifying a critical function of NRG1 in balancing brain activity (Wen et al., 2010).

DISRUPTED-IN-SCHZIOPHRENIA-1 (DISC1)

The Disrupted-in-Schizophrenia-1 (DISC1) gene was discovered in a large Scottish family in which a balanced chromosomal translocation [t(1;11)] segregates with schizophrenia, bipolar disease, major depression, and anxiety disorders (St Clair et al., 1990). The translocation t(1;11) (q42;q14) disrupts two genes named Disrupted in Schizophrenia 1 and 2 (DISC1 and DISC2). In contrast to DISC1, the function of DISC2 that encodes a non-coding RNA antisense to DISC1 is unclear. The existence of a clear, identifiable mutation has put DISC1 in a unique position in schizophrenia research (Chubb et al., 2008; Millar et al., 2001).

DISC1 is located within a chromosomal region that has been reported to harbor susceptibility genes for psychiatric illness in several populations (Ekelund et al., 2001; Hennah, 2005; Hennah et al., 2009). Several studies have also reported that healthy subjects and patients with schizophrenia carrying DISC1 variants have alterations in gray matter volume of the hippocampus and PFC (Callicott et al., 2005; Cannon et al., 2005), deficient memory and attention (Cannon et al., 2005; Hennah, 2005), and hippocampal or PFC activation (Callicott et al., 2005). Still, there are also negative reports for linkage to the DISC1 locus), SNP associations (Lim, 2009; Sanders, 2008; Wood, 2007), and the rearrangements within the DISC1 locus. Furthermore there is little support for the DISC1 locus in large association studies to date.

DISC1 protein likely acts as a scaffold protein, with multiple motifs mediating binding to several proteins (Camargo, 2007). DISC1 is expressed in adult rat heart, liver, kidney, brain, and thymus. Brain expression of DISC1 encompasses the hippocampal dentate gyrus, cerebral cortex, hypothalamus, amygdala, cerebellum, and olfactory bulbs (as reviewed in Chubb et al., 2008; Mackie et al., 2007).

RNAi knockdown of Disc1 in the embryonic cortex affects migration, produces mispositioning of neurons (Kamiya et al., 2005), decreases proliferation, and alters neuronal distribution in the developing cortex and adult hippocampus (Mao et al., 2009). In contrast, Disc1 knockdown in proliferating neurons in the mature dentate gyrus enhances migration, growth of dendrites and axons, and maturation of granule neurons. In addition, transient knockdown of DISC1 in the pre- and perinatal stages in pyramidal neurons of PFC leads to altered dopaminergic maturation and resultant behavioral abnormalities in adult mice (Niwa et al., 2010).

DISC1 mouse models have been instrumental in uncovering the mechanisms whereby this protein and its partners contribute to neurodevelopment with relevance to the pathogenesis of schizophrenia.

Risk Allele Model

Drs. Gogos and Karayiorgou have developed a Disc1 mouse model based on the 129 mouse strain, in which a spontaneous 25-bp deletion in exon 6 induces a frame shift in the open reading frame, resulting in 13 novel amino acids, followed by a premature stop codon in exon 7. This strain was modified by homologous recombination to have a termination codon in exon 8 and a premature polyadenylation site in intron 8 to produce a truncated transcript (Koike et al., 2006). Western blot analysis of brain extracts from mutant mice demonstrated the absence of two major Disc1 isoforms and the expression of short N-terminal isoforms (Koike et al., 2006). After backcrossing to the C57B6/j background, these mice show impaired working memory and no alterations in locomotion or PPI. Subsequent studies have found that mutants have disorganized newly born and mature neurons of the dentate gyrus and altered short-term plasticity. Recently, defects in axonal targeting and changes in short-term (Kvajo et al., 2008) plasticity at the mossy fiber/CA3 circuit have been presented for this mouse model as well as elevated levels of cAMP (Kvajo et al., 2011). Thus a natural polymorphism in Disc1 gene may be responsible for the neural and behavioral abnormalities reminiscent of schizophrenia.

Disc1 KO Mice

Generation of Disc1 knockout mice, lacking exons 2 and 3, has been recently reported (Kuroda et al., 2011). Mutant mice have no gross brain or behavior abnormalities but exhibit elevated anxiety and impulsivity (Kuroda et al., 2011). As expression of short transcripts in these KO mice is still observed, a mouse model with deletion of the entire genetic locus is needed to better decipher the function of DISC1.

ENU-Induced Model

Two mouse models based on mutations in the mouse Disc1 gene as a result of N-nitroso-N-ethylurea (ENU) mutagenesis were also described (Clapcote et al., 2007). Two novel missense mutations lead to Q31L and L100P amino acid exchanges in the exon 2, respectively. Notably, these mouse models are characterized by distinct phenotypes. 31L mice display increased immobility in forced swim test (FST), decreased sociability and social novelty, and decreased sucrose consumption, L100P mutants demonstrate increased locomotor activity, decreased PPI, decreased LI, and decreased performance in T-maze were found in L100P mutant mice. These models demonstrate that polymorphisms in Disc1 gene can produce variable behavioral alterations, consistent with distinct aspects of psychiatric disorders. Unfortunately, further study of some of the DISC1 models has not clearly substantiated some of the initially reported behavioral phenotypes (Shoji et al., 2012).

An analysis of the brain abnormalities in Disc1 mutants found a reduced neuronal number, decreased neurogenesis, and altered neuronal distribution and shorter dendrites and decreased surface area and spine density in cortical neurons of Disc1 L100P mutant mice (Lee et al., 2011). Genetic variations in DISC1 can influence interaction between PDE4, GSK-3, and DISC1 (Lipina et al., 2012).

The chromosomal translocation affects the C-terminal of the three major isoforms (Millar et al., 2001). Possible outcomes of the translocation in the DISC1 gene include haploinsufficiency or the production of a mutant truncated DISC1 protein. Expression of truncated human DISC1 in neuronal PC12 rat cells or mouse brain affects interacting partners via dominant-negative mechanisms, leading to altered levels and distribution of endogenous Disc1 (Kamiya et al., 2005; Pletnikov et al., 2008). In this context, studying effects of mutant DISC1 on neurodevelopment can provide valuable mechanistic insights into the pathogenesis of schizophrenia.

Constitutive Overexpression of Mutant DISC1

A transgenic mouse model with constitutive expression of mutant human DISC1 was developed (Hikida et al., 2007). Transgenic mice express mutant human DISC1 under regulation of the CAMKII promoter in forebrain neurons and exhibit elevated novelty-induced activity, impaired PPI, and more immobility in FST. Mutant mice also have decreased numbers of PV-positive neurons in the cortex and a transient enlargement of the lateral ventricles, demonstrating that forebrain neuronal expression of mutant human DISC1 can produce subtle neurobehavioral alterations resembling aspects of major psychiatric diseases (Hikida et al., 2007).

A BAC-transgenic mouse model with expression of C-terminus truncated mouse Disc1 under the endogenous Disc1 promoter was also described (Shen et al., 2008). These mice have thinning of the cortex, enlarged lateral ventricles, corpus callosum agenesis, impaired LI, and greater immobility in FST.

Inducible C-Fragment DISC1 Model

Silva and Cannon’s groups have introduced a DISC1 model in which the putative “translocated” C-terminus fragment of DISC1 is expressed under regulation of the CAMKII promoter in forebrain neurons in an inducible manner (Li et al., 2007). Remarkably, early postnatal but not adult expression of the fragment produces impaired performance in a DNMP task, attenuated social interaction, and a shorter latency to immobilization in FST. These behavioral changes were accompanied by reduced dendritic complexity and decreased basal synaptic transmission in the hippocampus. This inducible model was the first to demonstrate that early postnatal perturbation in Disc1 can lead to neurobehavioral changes, consistent with the neurodevelopmental hypothesis of schizophrenia.

Inducible Mutant Human DISC1 Model

A different mouse model of inducible expression of mutant human DISC1 in forebrain neurons was generated using the Tet-off system (Pletnikov et al., 2008). In this model, expression of mutant DISC1 is regulated by the CAMKII promoter and can be regulated with doxycycline. Expression of mutant DISC1 was described to produce no gross developmental defects but was associated with increased spontaneous locomotor activity in male but not female mice, decreased social interaction in male mice, enhanced aggressive behavior and poorer memory in Morris water maze task in female mice. In addition, expression of mutant DISC1 led to lateral ventricle enlargement in adult mice and reduced dendritic arborization in primary cortical neurons and decreased expression of a synaptic protein, SNAP-25, consistent with human postmortem studies that show decreased dendritic length and dendritic arborization in frontal cortical areas (Harrison, 1999).

To evaluate the roles of DISC1 at various stages of neurodevelopment, the effects of mutant DISC1 were examined during prenatal and/or postnatal periods. Regardless of timing of expression, decreased levels of cortical dopamine (DA) and fewer parvalbumin-positive neurons in the cortex were found in mutant mice. Combined prenatal and postnatal expression produced increased aggression and enhanced response to psychostimulants in male mice along with increased linear density of dendritic spines on neurons of the dentate gyrus of the hippocampus, and lower levels of endogenous DISC1 and LIS1. Selective prenatal expression was associated with smaller brain volume, whereas postnatal expression gave rise to decreased social behavior in male mice and depression-like responses in female mice as well as enlarged lateral ventricles and decreased DA content in the hippocampus of female mice, and decreased level of endogenous DISC1. Mutant DISC1 affects methamphetamine-induced sensitization and conditioned place preference: a comorbidity model (Pogorelov et al., 2012). The diverse changes in mutant DISC1 mice are reminiscent of findings in major mental diseases.

DISC1 models may be as relevant to bipolar disorder and psychotic depression as to schizophrenia.

MOUSE MODELS OF BIPOLAR DISORDER

The human genetics of bipolar disorder is perhaps less well established compared to that of schizophrenia. However, a number of genes have emerged from GWAS studies (Welcome Trust Case Control Consortium, 2007; Sklar et al., 2008; Craddock and Sklar, 2009; Lichtenstein et al., 2009; Schulze et al., 2009; Green et al., 2010; Curtis et al., 2011; Psychiatric GWAS Consortium Bipolar Disorder Working Group 2011; Sullivan et al 2012), and the hope is that as the power of these studies increases, additional candidate genes will be forthcoming. Furthermore, the increasing sophistication of genetic analyses is making it possible to suggest possible pathways (Pandey et al., 2012), including Wnt signaling circadian rhythm pathways, cadherin signaling pathway, axonal guidance, and neuroactive ligand-receptor interactions.

One of the notable themes emerging from current psychiatric genetics is the overlap between schizophrenia and bipolar disorder as well as the overlap between schizophrenia and autism. We hypothesize that risk for schizophrenia is more related to neurodevelopmental brain changes, whereas risk for bipolar disorder may be more related to neuronal signaling and plasticity.

CACNA1C

Voltage-gated calcium channels have emerged from these studies as strong genetic candidates, with overlap for both schizophrenic and bipolar disorder. There is extensive knowledge of the biology of voltage-gated calcium channels, which will not be repeated in detail here. They are critical for neuronal-­membrane-excitability regulated entry of calcium into cells, and are involved in regulation of many signaling pathways and activity related to gene transcription (Bhat et al., 2012). Intriguingly inhibitors of voltage-gated calcium channels have been used in treating bipolar disorder with some mixed success.

Mouse model studies related to voltage-gated calcium channels are just beginning to address issues of behavior related to psychiatric disorders. For instance, voltage-gated calcium channel CACNA1C haploinsufficiency was associated with decreased exploratory behavior, diminished response to amphetamine, and altered behavior in the forced swim and tail suspension tests with sex-specific differences (Dao et al., 2010). These studies though raise the issue of what mouse model is likely to be most appropriate given the human genetics. There is some genetic evidence that the genetic variation at the L-type calcium channel may be a partial gain of function. Thus, mouse models of the disorder may be most appropriately established using transgenic overexpression or other comparable genetic modifications.

ANKYRIN-G

Another very intriguing genetic association in bipolar disorder is with the ANK3 locus, which codes for the ankyrin-G protein. This was found to be the strongest risk factor in one of the initial GWAS studies or is replicated more modestly or variably in subsequent GWAS studies, but has more recently emerged again as a leading candidate gene in population studies.

Ankyrin-G is an especially intriguing candidate as it has well-established roles in maintenance of the structure of the axon initial segment, and in maintenance of axodendritic polarity in vivo (Pan et al., 2006; Roussos et al., 2012; Sobotzik et al., 2009; Zhou et al., 1998). Ankryin-G maintains voltage-gated sodium channels and potassium channels at the axon initial segment, and thus is critical for generation and regulation of the axon potential. It is also critical for axon potential transmission, since it is located at nodes of Ranvier as well. Intriguingly ankyrin-G also appears to be relevant for functional localization of dystrophin complexes (Ayalon et al., 2008), potentially suggesting the relationship between these two risk genes.

The genetic organization of the ankyrin gene locus is complex (Rueckert et al., 2012). Most of the bipolar disorder genetic variation at the ANK3 locus is in the promoter region, suggesting alterations of expression, though it is possible there are also alterations in splicing given the complex splice and promoter usage variation. Thus, for this gene again it is unclear what genetic manipulation may be most relevant to the human disorder; however, partial loss of function would appear to be a good candidate. There has been one knockout mouse model generated in which one of the isoforms has been deleted (Pan et al., 2006; Zhou et al., 1998). This isoform is highly expressed in cerebellum, so the animals have a significant degree of ataxia, making other behavioral tests difficult to interpret. Recent data suggest that these animals may have cognitive and emotional changes as well as motor changes. In addition, they have intriguing alterations in cerebellar circuitry. The loss of ankyrin-G expression in Purkinje cells leads to a redistribution of synaptic input onto Purkinje cells, presumably with profound alterations for neuronal connectivity in signaling. In addition, an ankyrin mouse model with knockout of most isoforms expressed in brain has recently been generated. A conditional knockout enables the deletion of ankyrin-G in the forebrain. Preliminary data suggest that this model may have hyperactivity and alterations in cognitive and emotional behavior consistent with some aspects of human psychiatric disorder.

NEUROCAN

Several studies have found strong associations between the Neurocan (NCAN) gene and bipolar disorder (e.g., Cichon et al., 2011). Neurocan is a component of the extracellular matrix in brain and CNS, expressed at highest levels around birth in the mouse, and may be involved with regulation of synaptic connectivity and plasticity.

A recent study (Miro et al., 2012) combined clinical analyses and mouse behavioral studies. Genotype/phenotype correlations were tested in patients with bipolar disorder, depression, and schizophrenia. Instead of using DSM4 diagnoses, the clinical features were factor-analyzed. In the combined patient sample, the NCAN risk allele was significantly associated with the “mania” factor, in particular “overactivity.” A mouse with genetic deletion of neurocan was available (Zhou et al., 2001), and had no gross developmental abnormalities, though altered synaptic transmission and plasticity had been observed. Behavior of the NCAN KO mice was then studied in more detail (Miro et al., 2012). The NCAN KO mice were hyperactive and showed more frequent “risk-taking” behaviors, less “depression-like” conduct, greater amphetamine hypersensitivity, and increased saccharin preference. These behavioral changes were ameliorated by lithium treatment.

DIACYLGLYCEROL KINASE

A locus that has recently been identified in relation to bipolar disorder is the diacylglycerol kinase DGK locus. Behavioral tests using DGK beta knockout mice showed hyperactivity reduced anxiety and reduced “depression”-like behaviors. These behaviors were attenuated by the administration of lithium. These mice also showed impairment in GSK3 beta signaling (Kakefuda et al., 2010). Taken together these data suggest that DGK beta knockout mice have some behavioral abnormalities that could be relevant to human psychiatric disorders, and these mice merit further study.

ODZ4

Recent GWAS studies have identified the ODZ4 or teneurin-4. Relatively little attention has been paid to this gene to date. A mouse mutation designated furue has some behavioral changes and substantial alterations in myelination of small diameter axons and differentiation of oligodendrocytes. Given that white matter changes have been detected in human psychiatric disorders, this model may also merit further study.

OTHER GENES AND PATHWAYS

There is some support for the role of circadian-rhythm-related genes in risk for affective disorder, though perhaps more for depression than bipolar disorder (Kennaway, 2010), and of course sleep and circadian rhythm disturbances are notable in human affective disorder. Several different mouse models of alterations of clock genes have been reported with changes in anxiety, exploratory behavior, activity, and cognitive behavior as well as alterations in circadian periodicity (Arey and McClung, 2012; Keers et al., 2012; Kozikoski et al., 2011; McClung, 2011). Pharmacologic data and some studies of gamma oscillations suggest possible translation to human psychiatric disorder (Dzirasa et al., 2011).

The beta-catenin pathway has recently emerged in genetic studies and also has pharmacologic data to support it. Interestingly, overexpression of beta catenin results in behavioral changes including alterations in the forced swim test and alterations in drug response (Gould et al., 2007).

Other studies have modeled pathways that may be relevant to psychiatric disorders such as the GSK3 beta pathway (Ackermann et al., 2010). Polymorphisms in DISC1 have also been reported to disrupt Wnt and GSK3 beta signaling (Singh et al., 2011).

It has been claimed that a mouse strain termed “Madison” shows behavioral changes reminiscent of mania. Gene expression array changes and drug responses may also be comparable to the human disorder; however, it is unclear if there is any genetic convergence with human genetic risk factors (Saul et al., 2012; Scotti et al., 2011).

As noted above, numerous studies have implicated glutamate signaling, and some studies have suggested that glutamate receptors are relevant for bipolar disorder (Knight et al., 2011). A number of studies of glutamate receptor mouse models have been generated. A detailed consideration of these studies is beyond the scope of this current chapter, since the genetic correlation is not clear. There is an extensive literature on dopamine transporter knockout mice. These have dramatic hyperactivity and other behavioral changes reminiscent of affective disorder. However, the relationship to the human genetics is still unclear.

FUTURE DEVELOPMENTS

Psychiatric genetics is still in its infancy, with replicable risk loci just beginning to be identified. Functional genomics studies, including better mouse models, will have greater opportunities when mutations with clear effects on gene transcription, splicing, translation, and regulation are identified. Even the knowledge of whether genetic variation leads broadly to loss or gain of function will be helpful, though either can lead to failure of neuronal homeostasis (Ramocki and Zoghbi, 2008). Although the current models have advanced our understanding of the neurobiology of schizophrenia and bipolar disorder, there are still many issues that need to be addressed in the future research.

The methodologies to manipulate the mouse genome at different levels of its organization are constantly improving (see Chapter 8). Simple knockout and transgenic technologies produce artificial systems with the deletion of one or both copies of a gene, or with its overexpression. New models with point mutations in coding sequence or mutations in regulatory elements will better reflect the complex molecular processes implicated in schizophrenia or bipolar disorder (Chen, 2006). The use of zinc finger nucleases and transcription activator-like effector nucleases to manipulate the genome (Cheng et al., 2012) may provide additional options. Inducible and conditional systems allow the alteration to be expressed in a time-dependent and specially controlled fashion.

A drawback of current mouse models is related to the fact that schizophrenia and bipolar disorder are polygenic diseases, and current techniques alter the genome one gene at a time. Combining multiple genetic mutations in a single model could be more informative. Attempts to model neuropsychiatric disorders based on gene expression changes (Lin et al., 2012) may be very difficult to interpret, but targeting several susceptibility genes that belong to different signaling pathways may be a promising direction. Once single gene models are well characterized, it may be possible to perform genetic crosses or other attempts to model polygenic inheritance.

Alternatively it may be possible to make single manipulations at key regulatory positions with pleomorphic effects.

An important aspect of the complex etiology of schizophrenia and bipolar disorder is a contribution of environmental factors (Brown, 2010; van Os et al., 2008). Combining both genetic and environmental risk factors by exposing genetically altered mice to adverse environments at different times across the life span of the mouse could better reflect the complexity of the pathogenesis of these diseases. Although still in infancy, the initial gene-environment interaction studies have already revealed some issues important for future research. For example, combining an environmental challenge with a genetic mutation in the susceptibility gene can produce both protective and pathogenic effects, depending on the type of adverse environment and the time of interaction. Combinations of genetic and environmental factors can also result in new phenotypes previously unseen in unchallenged mutant mice or wild-type mice exposed the environmental insult (Abazyan et al., 2010; Behan et al., 2012; O’Tuathaigh et al., 2010). Given that simple laboratory environmental changes could be responsible for appreciable variations in the mouse behavior (Crabbe et al., 1999), one needs to be extremely cautious in interpretations of the changes produced in genetic mouse models due to environmental factors.

TABLE 22.1. Behavioral tests used in animal models of schizophrenia (adapted from Nestler and Hyman 2010, used with permission)

TABLE 22.2. Behavioral tests used in animal models of mood disorders (Adapted from Nestler and Hyman 2010, used with permission)

Behavior readouts have limitations (see Tables 22.1 and 22.2 and Box 22.1). Many of the behavioral tests currently in use were developed for pharmacological studies. As new genetic and environmental models are developed, there should be an iterative process of developing and refining behavioral tests. Brain imaging, electrophysiology, or other endophenotypes are likely to provide additional information, which may be more translatable to the human diseases.

Most studies to date have focused on neuronal functions of susceptibility genes. However, many of the candidate genes are also expressed by glial cells (Iijima et al., 2009). Manipulation of expression in non-neuronal cells may be important. For example, a recent study has provided the first evidence for interaction between DISC1 and serine racemase in astrocytes, connecting DISC1 and d-serine/NMDA receptor hypofunction (Ma, 2012).

Thus, genetic mouse models will continue to be important tools for psychiatric research. They have been illuminating the functions of candidate genes in neurodevelopment and are stimulating a search for future pathogenic treatments. The approach of using factor analysis of human clinical phenotypic features, association with genetic risk loci, and then in turn correlating with phenotypes of mice with alterations at the same loci (e.g., Miro et al., 2012) is intriguing. More sophisticated and advanced genetic manipulations in combination with better understanding of the human clinical phenotypes will be needed to refine the present models to make them more relevant to human psychiatric diseases.

DISCLOSURES

Dr. Pletnikov has no conflicts of interest to disclose. He is funded by NIH only. Grant Support: NIH (P50MH084018 and 5R01MH083728–04).

Dr. Ross has no conflicts of interest to disclose.

Box 22.1

We propose the following considerations for future animal models of schizophrenia and bipolar disorder:

CONSTRUCT VALIDITY

• • Construct validity based on human genetic studies
• • Manipulation at a locus identified in human population genetic (e.g., GWAS or sequencing) studies
• • Manipulation using a specific causative point or deletion mutation
• • Copy number variation models
• • Construct validity based on human environmental studies
• • Human environmental stressors such as prenatal immune activation
• • Construct validity based on interaction of genetic and environmental factors

FACE VALIDITY

• • Behavioral Features
• • For schizophrenia
• • Behavioral and social changes (social withdrawal, anhedonia)
• • Cognitive deficits (working memory)
• • For affective disorder
• • Mania-like alterations, such as hyperactivity and hypersexuality, risk-taking behavior, and impulsivity
• • Depression-like behaviors
• • Altered circadian rhythms, sleep disorders
• • Endophenotypes
• • Structural brain change including lateral ventricle enlargement
• • Functional and chemical brain changes (e.g., fMRI, micro- PET, MRS)
• • Electrophysiological changes such as reduced N100, mismatch negativity (MMN), changed theta and gamma oscillation
• • Histological changes such as
• • Interneuron and synaptic pathology
• • Abnormal neurogenesis
• • Molecular and cell signaling changes

PHARMACOLOGICAL VALIDITY FOR EXISTING MEDICATIONS

• • Antipsychotics for schizophrenia models
• • Lithium and valproate for bipolar models
• • Antidepressant for depression models

PREDICTION OF NEW FEATURES THAT ARE SUBSEQUENTLY VALIDATED IN HUMAN

• • Novel endophenotypes
• • Novel neuropathology
• • Novel pharmacological targets

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