Elsevier

Behavioural Brain Research

Volume 204, Issue 2, 7 December 2009, Pages 282-294
Behavioural Brain Research

Research report
Prepulse inhibition and genetic mouse models of schizophrenia

https://doi.org/10.1016/j.bbr.2009.04.021Get rights and content

Abstract

Mutant mouse models related to schizophrenia have been based primarily on the pathophysiology of schizophrenia, the known effects of antipsychotic drugs, and candidate genes for schizophrenia. Sensorimotor gating deficits in schizophrenia patients, as indexed by measures of prepulse inhibition of startle (PPI), have been well characterized and suggested to meet the criteria as a useful endophenotype in human genetic studies. PPI refers to the ability of a non-startling “prepulse” to inhibit responding to the subsequent startling stimulus or “pulse.” Because of the cross-species nature of PPI, it has been used primarily in pharmacological animal models to screen putative antipsychotic medications. As techniques in molecular genetics have progressed over the past 15 years, PPI has emerged as a phenotype used in assessing genetic mouse models of relevance to schizophrenia. In this review, we provide a selected overview of the use of PPI in mouse models of schizophrenia and discuss the contribution and usefulness of PPI as a phenotype in the context of genetic mouse models. To that end, we discuss mutant mice generated to address hypotheses regarding the pathophysiology of schizophrenia and candidate genes (i.e., hypothesis driven). We also briefly discuss the usefulness of PPI in phenotype-driven approaches in which a PPI phenotype could lead to “bottom up” approaches of identifying novel genes of relevance to PPI (i.e., hypothesis generating).

Introduction

Prepulse inhibition (PPI) of startle is a cross-species measure that refers to the ability of a non-startling “prestimulus” to inhibit the response to a startling stimulus ([96]; neurobiological reviews [64], [190]). There have been numerous reports of PPI deficits in schizophrenia patients (for review see [19], [197]), their unaffected first degree relatives [29], and patients with schizotypal personality disorder [28]. In addition to decreased PPI observed in schizophrenia patients, several other neuropsychiatric disorders are associated with decreased PPI, including Obsessive-Compulsive Disorder [189], Tourette's syndrome [192], Huntington's disease [195], manic bipolar patients [153], Panic Disorder [129], and adults with autism [154]. Thus, while there are several neuropsychiatric disorders that display decreased PPI compared to normal controls, PPI deficits in schizophrenia patients are the best characterized and the most widely replicated [19], [114], [128], [130], [197].

While the meaning of deficient or reduced PPI for an organism has been debated, Swerdlow et al. [197] have argued persuasively that it is a useful psychophysiological process for basic studies in humans and animals to probe neural circuitry and as a pharmacological screen. Additionally, PPI of startle has been suggested as a potentially useful endophenotype with which to understand the genetics of schizophrenia [18], meeting the criteria outlined for a viable endophenotype by Turetsky et al. [205]. Specifically, the endophenotype should be heritable, present in unaffected relatives, associated with a disorder with good test re-test reliability, able to be measured rapidly and easily, and have a discrete neurobiological basis that is related to the pathophysiology and genetics of a disease [205]. Hence, many in the field of schizophrenia genetics have focused primarily on neurophysiological measures such as PPI, P50 auditory evoked suppression, antisaccade eye movement, mismatch negativity, and P300 event related potential [205]. The assertion that PPI may be a useful endophenotype in genetic studies of schizophrenia, combined with the observation that PPI has a strong genetic component in mice [55], suggests that PPI may be a useful behavioral phenotype to consider in genetic mouse models related to schizophrenia. While there are certainly many other symptoms and deficits observed across the heterogeneous group of patients with schizophrenia, PPI appears to be a viable endophenotype for genetic studies and thus a reasonable approach to investigate in animal models of the genetics of schizophrenia. Mutant mouse models related to schizophrenia have been based primarily on the pathophysiology of schizophrenia, the known effects of antipsychotic drugs, and candidate genes for schizophrenia. In this review, we provide a selected overview of PPI in mouse models of schizophrenia and discuss the contribution and usefulness of PPI as a phenotype in the context of genetic mouse models. In a 2002 review of genetic mouse models of PPI, Geyer et al. [66] summarize studies of strain differences in PPI, genetic mutants, and the pharmacology of PPI in mice. More recently, there have been two particularly relevant reviews on mouse models of susceptibility genes for schizophrenia [143] and mouse models of altered PPI [197]. Hence, in order to avoid redundancy with these previous reviews, in the current review we highlight a few of the approaches to genetic mouse models of schizophrenia and discuss some of the important caveats to these approaches. To that end, we discuss mutant mice generated to address hypotheses regarding the pathophysiology of schizophrenia and candidate genes (i.e., hypothesis driven). We also discuss the usefulness of PPI in phenotype-driven approaches in which a PPI phenotype could lead to “bottom up” approaches of identifying novel genes of relevance to PPI (i.e., hypothesis generating).

Many reports in the literature argue that PPI in animals models the positive symptoms of schizophrenia. This conceptualization stems primarily from the observation that drug-induced deficits in PPI are produced by psychotomimetic drugs such as amphetamine and PCP, and that drug-induced PPI deficits are reversed by first generation antipsychotics, which are all dopamine D2 receptor antagonists. In a recent review, Jones et al. [103] nicely outline the animal models that map onto the clinical symptoms of schizophrenia and accurately point out that there are no suitable animal analogs of hallucinations or delusions. Jones et al. [103] do suggest that two other “positive symptoms”, psychomotor agitation and grossly disorganized behavior, may be assessed in animals through measures of locomotor response to novelty and patterns of motor activity, respectively. The misconception that PPI is a measure of the positive symptoms of schizophrenia most likely stems from the fact that models of PPI deficits (e.g., pharmacological disruptions) have been relatively successful in predicting antipsychotic medications, which are fairly effective at treating the positive symptoms of schizophrenia and less effective, if at all, at treating the negative symptoms and cognitive deficits in schizophrenia. Historically, of course, most drug development efforts have focused on the identification of antipsychotic treatments for the positive symptoms of schizophrenia, given that only these criteria were used to evaluate potential treatments for use in patients with schizophrenia.

Attempts to correlate PPI deficits with positive and negative symptoms have yielded mixed results [200]. Some studies have reported negative correlations between PPI and thought disorder [139], [151], [152] or distractibility [109] in schizophrenia. In a recent study comparing cognitive function with PPI in over 300 subjects, there were no correlations between PPI and cognition as measured by traditional “pen and paper” tests (i.e., Wisconsin Card Sorting Task [WCST], California Verbal Learning Task, etc.), however, there was a positive relationship between PPI and Global Assessment of Function (GAF) and Independent Living scales [193]. Nevertheless, studies assessing behavioral measures reflecting cognitive constructs have demonstrated relationships to PPI performance. For example, converging evidence indicates that PPI is correlated with strategy formation and execution time in the Cambridge Neuropsychological Test Automated Battery (CANTAB) in healthy controls [12], [43], [68], a finding which should be further examined in patients with schizophrenia. Further work is needed to specify the aspect of cognitive function that might be best related to gating processes such as PPI [215]. For example, the CNTRICS (Cognitive Neuroscience measures of Treatment Response of Impaired Cognition in Schizophrenia) program funded by the National Institute of Mental Health considered PPI to provide a measure of the cognitive construct of “gain control” as a specific aspect of the perceptual abnormalities seen in patients with schizophrenia [83]. The series of CNTRICS workshops concluded that PPI may have utility as a biomarker for use in proof of concept studies of potential treatments for the cognitive deficits in schizophrenia that are not ameliorated by existing antipsychotic drugs.

For the purpose of evaluating a genetic mouse model of schizophrenia, the more useful comparison to make is not between PPI and specific symptoms of schizophrenia but rather the relationship between a gene and the observable dependent measure, i.e., PPI. As mentioned above, PPI has been suggested to meet the criteria as an endophenotype for genetic studies of schizophrenia [205]. The approach of using endophenotypes in schizophrenia in genetic studies has greatly strengthened the ability to conduct cross-species translational studies by providing specific observables or endophenotypes for study in experimental animals (reviewed in [65], [80]). Useful endophenotypes in this context are measures that are observed in humans and can be measured in mice.

Genetic manipulations have the potential to increase our understanding of the neural circuitry of neuropsychiatric disorders. A PPI deficit could indicate that the gene may be involved in the neural circuitry know to modulate PPI (e.g., cortical, limbic, striatal [190]); in other words it could function as a “surrogate measure for neural processes” as Swerdlow et al. [197] argue. For example, if a mouse is developed for a schizophrenia candidate gene with a relatively unknown function (or at least not an obvious relationship to schizophrenia pathology) and this mouse exhibits a PPI deficit, this may be an indication that limbic or striatal circuitry is altered. While a PPI deficit per se is not indicative of altered striatal or limbic circuitry, the presence of the deficit may suggest that these brain regions are affected by the genetic manipulation and provide a reasonable starting place for further hypothesis testing regarding the neurobiological implications of the genetic manipulation. Of course any evaluation of a PPI phenotype should be considered in the context of a thorough assessment of physical and sensory abnormalities (e.g., hearing loss), as pointed out in [66].

Mutant mouse models offer the opportunity to screen putative antipsychotics that may involve a novel target. Most pharmacological studies of PPI are based primarily on the ability of a drug (e.g., dopamine D2 antagonist) to reverse a drug-induced deficit in PPI (e.g., D2 agonist; [64]). This approach can lead to what some have called “receptor tautology,” meaning that a model based on the disruptive effects of a dopamine D2 agonist may only be able to predict drugs that act as D2 receptor antagonists. Using mutant mice to screen for putative antipsychotics may provide a means to develop novel drug targets. Several important examples of mutant mice being used to test putative antipsychotics are reviewed in subsequent sections.

Based on the diathesis-stress model of schizophrenia, which postulates that a genetic susceptibility coupled with environmental factors may be required for the full manifestation of the disease [79], studies of gene–environment interactions may be particularly informative for schizophrenia. Three ways in which genetics and environmental manipulations have been utilized in genetic mouse models are (1) using a mutant (e.g., knockout, KO) to delineate the mechanism of an environmental manipulation; (2) rescuing a phenotype in a mutant with an environmental manipulation; or (3) potentiating or unmasking a phenotype in a genetic mutant with an environmental manipulation (i.e., addressing the two-hit model of schizophrenia). There are a few examples in which PPI has been a useful endpoint with which to assess gene–environment interactions in mouse models of schizophrenia. For example, maternal immune activation (MIA) with PolyI:C during mid-gestation typically leads to deficits in PPI in adult offspring [140], [178]. Interleukin (IL)-6 KO dams exposed to MIA during mid-gestation are insensitive to the effects of MIA (i.e., exposed offspring do not show deficits in PPI; [181]). Hence, PPI in a genetic mutant (IL-6 KO mice) was used to determine the mechanism for the effects of immune activation on brain development. An example of a PPI phenotype being “rescued” in a KO mouse comes from studies in phospholipase C-β1 KO mice, in which PPI deficits and locomotor hyperactivity were attenuated in KO mice by environmental enrichment or clozapine [137]. While these are examples in which a genetic manipulation and an environmental manipulation interact, not all of these are true examples of gene–environment interactions in the sense of a “two-hit” hypothesis for schizophrenia. A good example of the “two-hit” approach are nuclear receptor null Nurr1 heterozygous mice, which display reduced mesocortical and mesolimbic dopamine [50] and reduced PPI following postnatal isolation rearing, an effect not observed with either isolation rearing or genotype alone [51]. This study provides a good example of the utility of PPI in gene–environment models relevant to schizophrenia, specifically those designed to test the “two-hit” hypothesis for the etiology of schizophrenia. It should be kept in mind, however, that many studies assessing gene–environment effects are evaluating additive effects of two manipulations and must be interpreted with caution.

When evaluating the role of a susceptibility gene implicated in the pathophysiology of schizophrenia, it is important to consider what criteria should be placed on a genetic/etiological model. In the present context, it is relevant to consider whether or not deficient PPI is a necessary phenotype with which to evaluate the usefulness of a targeted gene deletion of potential relevance to schizophrenia. Failure to see a PPI deficit in a mouse model may indicate a “false negative” particularly if other key behaviors relevant to schizophrenia are observed. For example, if a genetic mouse model shows deficits in social interaction and disturbances in performance on cognitive tasks such as attentional set shifting, but no differences in PPI, this does not indicate that the genetic model is not of relevance to schizophrenia. In other words, lack of a PPI phenotype should not “kill” a putative genetic model of schizophrenia. The likelihood of being able to represent all aspects of a heterogeneous disease in another species with a genetic mutation (most often a single gene deletion) is very rare if not impossible. In a recent review, Jones et al. [103] quote George Box, an industrial statistician, who said that “all models are wrong, some are useful” [16] and suggest that support for a model should be based on the convergence of data from multiple sources (e.g., many animal models, human genetic studies, etc.). Thus, no one phenotype should be considered as being neither necessary nor sufficient to support a model for schizophrenia. Along these same lines, Swerdlow et al. [197] point out that schizophrenia patients with functional impairments may have PPI in the normal range because of the overlapping PPI distributions between healthy volunteers and schizophrenia patients, and thus an animal model should not be rejected based on “normal” PPI.

Alpha-7 (α7) nicotinic acetylcholine receptor (nAChR) KO mice provide a good example of a schizophrenia susceptibility gene in which mutant KO mice display some phenotypes of relevance to schizophrenia in the absence of a PPI phenotype. Based on a genetic association between the α7 nicotinic receptor and schizophrenia, decreased expression of α7 nAChR in brain regions associated with schizophrenia, and the high prevalence of smoking in schizophrenia patients, α7 nAChR KO mice have gained importance in our understanding of the pathophysiology of schizophrenia [56], [134]. In fact, genetic studies have implicated the α7 nAChR gene (CHRNA7) in auditory P50 gating [57], [119], [135]. In an attempt to understand the relationship between auditory P50 gating and PPI, several groups have examined the relationship between the two forms of “gating” through correlational analysis in humans and rats (summarized in [145]). While P50 gating deficits and PPI deficits are reported in schizophrenia patients, often in the same group of patients, data from these studies suggest that there is a divergence of PPI and P50 gating measures in schizophrenia patients and healthy controls [20], [145]. PPI and N40 gating, the rodent analog of P50 gating, also appear to diverge from each other when measured contemporaneously in rats [191]. Hence, the divergence of gating measures within schizophrenia patients and the overlapping distributions of PPI between schizophrenia patients and controls, suggests that PPI in animal models should not be used as the sole indicator of a schizophrenia-relevant phenotype. For example, α7 nAChR KO mice do not exhibit deficits in PPI [150]. They do, however, show impaired performance in delayed non-matching to sample tasks [52] and deficits in attention as measured by the 5-choice serial reaction time task [214]. Thus, the lack of a PPI phenotype in α7 nAChR KO mice should be evaluated in the context of other behaviors relevant to schizophrenia in these mice, the strong association between α7 nAChR and auditory gating, and the divergence of gating measures in schizophrenia.

Along the same lines, there is the possibility that a PPI deficit in a mutant mouse model could represent a “false positive”, in which a PPI phenotype may be suggestive of an association between that gene or pathway and schizophrenia and no such association is found. We would argue that the PPI phenotype should be interpreted as meaning that the given genetic manipulation may be involved in the regulation of PPI expression and caution that PPI phenotypes should not be automatically associated with schizophrenia. One example of a way to test for a “false positive” would be to examine whether or not the PPI deficit could be reversed with existing antipsychotic drugs.

Section snippets

Models of pathophysiology

Mutant mouse models of the pathophysiology of a disorder can be considered to reflect hypothesis-driven approaches. These models are based either on a known or a hypothesized neuropathology. The main approaches that will be reviewed here are based primarily on the pharmacology of psychotomimetic drugs, namely the glutamate and dopamine hypotheses of schizophrenia, and on evidence of GABA dysfunction in schizophrenia brains. Other approaches to modeling the pathophysiology of schizophrenia

Genetic mouse models as pharmacological tools

Historically, animal models of relevance to schizophrenia have been driven primarily by studies combining pharmacological inducing conditions (e.g., PCP) paired with relevant dependent measure(s) (e.g., PPI; locomotor hyperactivity; latent inhibition). Most of that literature is based on studies in rats and is reviewed extensively elsewhere [67]. These pharmacological models have been instrumental in establishing three of the most prominent theories of schizophrenia, the dopamine hypothesis [40]

Candidate gene approach: “Top-Down” approach

Heritability estimates for schizophrenia range from 24 to 80% depending on whether the studies used diagnosis or endophenotypes in the estimations [32], [84], [188]. Linkage studies have identified several chromosomal regions and candidate genes thought to be involved in the pathogenesis of the disease (reviewed in [86], [87], [187]). As the field of schizophrenia genetics has developed, several gene targets have been identified consistently and have thus been modified in mouse models through

Hypothesis generating: “Bottom-Up” approach

What can a PPI phenotype tell us about novel genes for schizophrenia? The field of molecular genetics continues to produce new mutant mouse models with unknown effects on the central nervous system. Many of these mutants have behavioral abnormalities that have been observed anecdotally. One such example of the way a novel gene of relevance to psychiatric conditions can be discovered through the creation of a mutant mouse is the SP4 gene. SP4, a member of the Sp1 family of transcription factors,

Discussion

Mutant mouse models of schizophrenia provide a unique way to assess the function of a susceptibility gene, test hypotheses about the pathophysiology of the disease, address treatment mechanisms of antipsychotic drugs, and generate hypotheses about the function of relatively unknown genes. In this review, we provided a brief overview of PPI deficits in some of these approaches and present specific examples where appropriate. As mentioned above, it is not likely that all aspects of a

Acknowledgements

We thank Dr. Victoria Risbrough for her helpful comments. This work was supported by grants from the National Institute of Mental Health (R01MH073991, R01MH52885) and by the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.

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