Schizophrenia is a chronic debilitating neuropsychiatric disorder affecting approximately 1% of the population worldwide. Symptoms cluster into three categories: positive (including auditory and visual hallucinations, delusions, conceptual disorganization and thought disorder), negative (emotional blunting, social withdrawal, anhedonia, avolition, poverty of thought and content of speech) and cognitive dysfunction (including impaired executive function, working memory and attention) (Andreasen, 1995). Patients present with extremely heterogeneous symptom combinations, making diagnosis and treatment problematic. Many patients undergo prolonged periods of remission interspersed with relapses of psychotic episodes. Disease onset is typically post adolescence (16–25 years), with a higher incidence of psychotic symptoms in males and a bimodal later onset (40–60 years) in females. Although the aetiology of schizophrenia remains contentious, it is a multifactorial neurodevelopmental disorder influenced by both genetic and environmental factors (Lewis and Lieberman, 2000; van Os et al., 2010), such that monozygotic siblings of affected individuals show a 50–80% risk of developing the disorder.
The first drugs, found by serendipity rather than design in the 1950s, to treat the psychotic symptoms of schizophrenia (haloperidol and chlorpromazine, called classical neuroleptics) are also known as the first-generation antipsychotics. The second-generation or atypical antipsychotics, so called because of their different clinical profile (including clozapine, olanzepine, risperidone and aripiprazole) developed from the 1970s have less tendency to produce unwanted extrapyramidal side effects and hyperprolactinaemia (Remington, 2003). While first-generation antipsychotics are classified according to chemical structure, the second-generation antipsychotics are characterized according to their pharmacology. These drugs were developed to treat the positive (psychotic) symptoms and not the negative or cognitive impairments. However, multi-site, double-blind studies comparing several second-generation antipsychotics with a typical antipsychotic, perphenazine, failed to substantiate any major therapeutic advantage of the former (Lieberman et al., 2005). The cognitive symptoms of schizophrenia often precede the occurrence of psychosis, and their treatment is considered a better predictor of therapeutic outcome (Mintz and Kopelowicz, 2007). However, while positive symptoms are currently treated to a varying degree by typical and atypical antipsychotics, the negative, and in particular, the cognitive impairments, remain resistant to treatment with current antipsychotics even after remission of the psychosis (Nuechterlein et al., 2004; Keefe et al., 2007; Mintz and Kopelowicz, 2007). Consequently, there is an urgent need to develop novel compounds that demonstrate increased efficacy against cognitive dysfunction and negative symptoms most likely by the use of adjunct therapy in combination with existing antipsychotics. In recognition of this problem, the US National Institute of Mental Health, in partnership with the US Food and Drug Administration and academic partners developed the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) initiatives to attempt to establish a reliable, valid and consensus-derived method of assessing cognition, and improve the likelihood of successful development of new compounds that could be used alongside existing drugs to more effectively treat the cognitive and negative symptoms of schizophrenia (see http://www.MATRICS.ucla.edu and http://www.turns.ucla.edu). The MATRICS initiative identified seven core domains of cognition: working memory, attention/vigilance, reasoning and problem solving, processing speed, visual learning and memory, verbal learning and memory, and social cognition, that are deficient in schizophrenia which have to be treated to meet therapeutic needs, and recommended a specific neuropsychological test battery to characterize these domains. A development of this initiative is the evaluation of the clinical relevance and predictive value of existing preclinical cognitive tasks and agreement for the need to develop a preclinical cognitive test battery to aid drug development (Hagan and Jones, 2005; Nuechterlein et al., 2005). Floresco et al. (2005) suggested using two approaches in experimental animals: lesions or drugs to manipulate specific systems altered in schizophrenia and developing models with cognitive deficits that resemble those seen in the disorder, to improve translational reliability of data obtained. Young et al. (2009) extensively reviewed existing animal cognitive paradigms and critically appraised their translational relevance to the seven human cognitive domains identified as being affected in schizophrenia. However, such cognitive paradigms need to be examined, not just in normal healthy animals, but in credible validated models of the disorder which will be reviewed in this paper.
Animal models of complex heterogeneous psychiatric disorders are clearly very valuable preclinical tools with which to investigate the neurobiological basis of the disorder. They offer a more rapid platform to monitor disease progression than in humans, and the opportunity to perform invasive monitoring of structural and molecular changes that underlie the cause of the disease and test novel therapeutics not possible in patients. However, a perplexing problem is how to assess some of the core symptoms of psychiatric disorders (like thoughts, and verbal learning and memory), which are uniquely human traits (Powell and Miyakawa, 2006). In general, most behaviours can only be indexed rather than directly quantified, and we are left to monitor performance in tasks designed to have translational relevance to core symptoms and make inference about the psychiatric state. A further problem with models of schizophrenia is that there is no current ‘gold standard’ medication available to treat all the symptoms that can be used as a definitive positive control in preclinical studies, although drugs like haloperidol and clozapine should reverse behavioural correlates of positive symptoms. Furthermore, many of the current antipsychotics may have a small therapeutic window of effect before sedation and other non-specific motor suppressant actions confound interpretation in tasks designed to assess negative and cognitive function (against which in any case these drugs have limited therapeutic effect).
All useful animal models should have the appropriate triad of face (symptom homology), construct (replicate the theoretical neurobiological rationale and pathology) and predictive (show the expected pharmacological response, or lack of it, to treatment by known antipsychotics and potential new adjunct therapies yet to be developed) validity to the clinical disorder being modelled. For schizophrenia, a suitable constellation of behavioural and neurochemical abnormalities would include postpubertal onset, loss of hippocampal and cortical connectivity and function, limbic dopamine dysregulation, cortical glutamatergic hypofunction, vulnerability to stress, abnormal response to reward, social withdrawal and cognitive impairment (Figure 1). Several recent articles (Floresco et al., 2005; Hagan and Jones, 2005; Fone and Porkess, 2008; Millan and Brocco, 2008; Bellon et al., 2009; Neill et al., 2010) have reviewed individual animal models of schizophrenia or compared the potential application of some of the common models with emphasis on their predictive validity to evaluate novel compounds that could improve the cognitive and negative symptoms seen in schizophrenia.
Recently, it has been estimated that over 20 different animal models of schizophrenia have been developed (Carpenter and Koenig, 2008), although several have considerable overlap in the methodology/principle used, and all fit into four different induction categories: developmental, drug-induced, lesion or genetic manipulation, as will be discussed in this review. Initial animal models were developed on the basis of the tenet theory that dopamine dysfunction was central to the pathophysiology of schizophrenia, but with increased understanding of the genetic basis and potential involvement of glutamate animal models have also been developed to explore their involvement in the disorder. Most rodent models of schizophrenia tend to replicate aspects of the positive symptoms of schizophrenia (Table 1), such as hyperactivity probably reflecting enhanced mesolimbic dopamine function, but some, including methylazoxymethanol (MAM), neonatal hippocampal lesion, isolation rearing from weaning and chronic phencyclidine (PCP) administration, show cortical dopaminergic dysfunction and sensori-motor gating deficits that may be the consequence of altered development of frontal cortical–limbic circuits. Treatment of the negative and cognitive symptoms of schizophrenia is a vital and unmet clinical need that could have a major impact on patient recovery and re-integration into society. Therefore, the development of more comprehensive models that more adequately replicate deficits in these symptoms and help to understand causal factors is ongoing, but many of the models remain to be tested, as reviewed herein.
|Animal model||Basal- and drug- induced locomotor activity||Sensorimotor gating||Cognition||Social interaction||Structure and neurochemistry||Antipsychotic reversal|
|Gestational MAM (GD17) (Moore et al., 2006; Lodge et al., 2009)||Spontaneous hyperactivity in novel arena emerging at puberty. Enhanced amphetamine- and NMDA antagonist-induced locomotion.||Deficit in PPI appears at puberty.||Normal acquisition, but impaired re-learning in the Morris water maze; impaired extra-dimensional shift in attentional set-shifting task||Reduced total social interaction appears prior to puberty.||Reduced PFc and hippocampal size, enlarged ventricals, reduced hippocampal soma size and neuropil; enhanced nAcc DA release; spontaneously hyperactive VTA DA neurones; decreased PFc parvalbumin GABA interneurones||No pharmacological reversal of behaviour attempted. CLZ does not reverse change in BDNF.|
|Post-weaning social isolation (Lapiz et al., 2003; Fone and Porkess, 2008)||Hyperactivity in a novel arena appearing 2–3 weeks after commencing isolation; hyper-responsivity to amphetamine and cocaine together with increased nAcc DA release||Persistent, but strain-dependent reduction in PPI to acoustic startle appearing about 6 weeks after isolation||Deficit in novel object recognition; no effect on acquisition of spatial learning by impaired reversal learning in water maze, extra-dimensional shift in the attentional set-shifting task and fear-motivated conditioned emotional response||Increased aggression and increase in total social interaction||Reduced PFc volume; reduced dendritic spine density, cytoskeletal alteration and loss of parvalbumin-containing interneurones and reelin in the hippocampus; reduced PFc D1 binding, no change in striatal D2 density, but increased proportion of striatal D2High; increased spontaneously active VTA DA neurones||PPI reversed by atypical antipsychotics, D2 antagonists, α7-nicotinic agonists; novel object discrimination impairment reversed by 5-HT6 antagonists and mGluR2/3 agonist|
|Amphetamine models (Featherstone et al., 2007a; Featherstone et al., 2008; Sarter et al., 2009)||Sensitization of locomotor response to amphetamine||Persistent deficit in PPI dependent on dosage regimen||Deficits in attention and the attentional set-shifting task; hippocampal-dependent memory unimpaired||No reduction in social interaction||Enhanced mesolimbic DA response; altered ACh function in PFc||Locomotor sensitization blocked by CLZ and HLP; moderate attenuation of attention impairment by CLZ and HLP|
|PCP models (Jentsch and Roth, 1999; Phillips et al., 2001; Mouri et al., 2007; Neill et al., 2010)||Sensitization of locomotor response to PCP; hyper-responsive locomotor response to amphetamine and mild stress||No sustained deficit in PPI||Deficits in novel object recognition, attentional set shifting and T-maze delayed alternation||Reduced frequency and duration of primate social behaviour||Reduced basal and stress-induced PFc DA and glutamate release; decreased synaptic spines on Fc neurones and cortical and hippocampal parvalbumin-positive neurones||Deficits in reversal learning reversed by atypical antipsychotics but not HLP; locomotor sensitization attenuated by CLZ and HLP|
|Neonatal ventral hippocampal lesion (Lipska, 2004; Tseng et al., 2009)||Locomotor hyper-responsivity to stress, amphetamine and NMDA receptor antagonists; enhanced apomorphine-induced stereotypy||Adult onset deficit in PPI||Impaired acquisition of T-maze delayed alternation and water maze; impaired radial arm maze choice accuracy; selective deficit in extra-dimensional shift and reversal in the attentional set-shifting task||Deficits in social interaction with increased aggression at all developmental ages||Unaltered basal nAcc DA release, but enhanced response to stress or amphetamine; reduced mPFc NAA levels and GAD67 mRNA expression||Amphetamine-induced hyperactivity reversed by acute or chronic antipsychotic injection; social interaction deficit not reversed by CLZ|
|DISC-1 knock-out (Jaaro-Peled, 2009)||Hyperactivity seen in L100P, CaMK-ΔC mutants, but not in others; no data available regarding psychostimulant-induced locomotor activity to date||Deficits in PPI seen in some (e.g. constitutive CaMK-ΔC, L100P, Q31L), but not all mutants (e.g. inducible CaMK-ΔC, Δ25 bp); PPI not tested in CaMK cc or BAC ΔC mutants||Impaired T-maze performance seen in most strains; impaired spatial working memory only seen in female CaMK-ΔC inducible mutants||Reductions in social activity seen in some strains (e.g. Q31L) and some CaMK- ΔC transgenics||Reduced brain volume in most strains; enlarged lateral ventricles, reduced hippocampal and PFc dendritic density, structure and complexity in some strains; reduced hippocampal parvalbumin immunoreactivity in some, but not all mutants||PPI deficits in L100P mice reversed by HLP and CLZ|
|Neuregulin1 and ErbB4 knock-out (Harrison and Law, 2006a; Mei and Xiong, 2008)||Most, but not all, neuregulin and ErbB4 mutants show spontaneous locomotor hyperactivity, but inconsistent responses to psychostimulants||PPI deficits seen in most neuregulin mutants reviewed; ErbB4 mutants show normal PPI||Impaired contextual fear and mismatched negativity performance in some mutants||Some deficits in social interaction, increased aggression and reduced responses to social novelty||Increased lateral ventricles and reduced hippocampal spine density; reduction in functional forebrain NMDA receptors||Spontaneous and psychostimulant-induced locomotor hyperactivity reversed by CLZ in Nrg1(ΔTM)+/− and Nrg1(BACE)−/− mutants|
|Dysbindin knock-out (Karlsgodt et al., 2011; Papaleo et al., 2010)||Spontaneous locomotor hyperactivity and hyper-responsivity to amphetamine challenge||Increased PPI and startle response shown to be reversed by quinpirole, but not eticlopride||Increased acquisition of T-maze task; impaired spatial reference memory and novel object recognition performance||Reduced social contact during social interaction task||Hyperexcitability of PFc pyramidal neurones; altered synaptic structure and formation; elevated HVA/DA ratio in cortico-limbic regions||No data on antipsychotic reversal|
|Reelin knock-out (Krueger et al., 2006; Tueting et al., 2006)||Reduced locomotion in an open field; enhanced response to methamphetamine||Variable PPI responses, highly dependent on strain, environment and testing protocol||Few memory deficits reported; normal reversal learning and inhibitory control, normal MWM performance; some learning deficits in acquisition of operant tasks||Some modulation of social activity in novelty and/or interaction tasks||Increased neuronal packing and decreased dendritic spine density in PFc and hippocampal neurones||Normalization of reduced spontaneous activity by OLZ|