Animal genetic models of OCD are currently in the early stages of development and validation. The models reviewed here evaluated the effects of genetic manipulation or genetic diversity on behavioral measures with face validity for an aspect of OCD. These behavioral measures consist of various forms of compulsive or stereotypic behavior that provided a heuristic starting point for developing a model of OCD. Some of these models have also established some degree of predictive validity for OCD with respect to epidemiological factors, neural circuitry, or drug treatment effects. Future work further examining the predictive validity of these models will be critical for establishing their usefulness as models for studying mechanistic aspects of OCD.
Although face validity can provide a heuristic starting point for developing a novel animal model for a disorder, face validity based on subjective arguments, is often disagreed upon, and cannot be used to validate a model. Animals’ behavior in the models reviewed presently could be argued to show face validity for compulsive behaviors in OCD. For example, barbering, overgrooming, self-mutilation, chewing non-nutritive objects, somersaulting or flipping, repetitive jumping, pattern running, rigid syntactic grooming chains, and compulsive wheel running have been suggested by some to resemble certain OCD symptoms such as compulsive washing and ritualistic behaviors. Although these mouse behaviors may have phenomenological similarities with compulsions in OCD, only experiments testing the effects of variables with known effects in OCD (i.e. SRIs) in the model can determine which of these behaviors share similar fundamental underlying mechanisms with compulsions in OCD. For example, chronic SRI treatment has been shown to reduce spontaneous stereotypy in deer mice (Korff et al., 2008
) drug-induced perseveration in the T-maze (Yadin et al., 1991
) and opiate-induced oral stereotypy (Wennemer and Kornetsky, 1999
); however, chronic SRI treatment does not prevent other types of repetitive behaviors such as apomorphine-induced stereotypy (Rurak and Melzacka, 1985
), baseline grooming behavior (Yalcin et al., 2008
), and quinperole-induced compulsive checking (Szechtman et al., 1998
). In summary, only empirical testing can determine which forms of repetitive behavior show predictive validity for OCD.
Some of the models reviewed here show some predictive validity for OCD with respect to epidemiological factors, neural circuitry, or drug treatment. For example, spontaneous barbering shows several epidemiological commonalities with OCD including sex ratio, prevalence by age, and increased incidence associated with reproductive events (Garner et al., 2004
). Abnormal compulsive and stereotyped behaviors in Sapap 3 KO mice (Welch et al., 2007
), DICT-7 (Smicun et al., 1999
; Nordstrom and Burton, 2002
), DAT KD (Berridge et al., 2005
), and deer mice (Korff et al., 2008
) were directly or indirectly linked with altered functioning of fronto-subcortical circuitry which has been implicated in OCD. However, knowledge regarding the specific abnormalities in fronto-subcortical circuitry in OCD remains limited. Abnormal activity within these circuits detected in human imaging studies could result from primary pathology elsewhere in the brain, and recent data suggest that different subtypes of OCD may have different types of brain abnormalities (Mataix-Cols et al., 2004
). Thus, demonstrating involvement of fronto-subcortical circuitry in putative animal model of OCD does not necessarily contribute to the predictive validity of the model. Undoubtedly, such findings still provide valuable insights into the control of compulsive behavior, and could generate testable hypotheses for studies of OCD patients.
Some of the models reviewed here showed sensitivity to drug treatments that are effective in OCD. For example, stereotyped behavior of deer mice housed in laboratory conditions was substantially reduced by chronic (3 week) SRI treatment. Furthermore, chronic treatment with the tricyclic antidepressant desipramine, which is ineffective in OCD, did not alter stereotypic behaviors in deer mice (Korff et al., 2008
). If future studies show that short-term treatment with SRIs does not reduce stereotypic behavior in deer mice, this model will demonstrate strong predictive validity as a model of OCD that is sensitive to effective therapeutics as well as their time course of action. Testing the behavioral effects and the time course of action of SRIs and other antidepressants provides one of the most straightforward means to test the predictive validity of a novel model of OCD, because the effects of these drugs have been so well characterized by numerous double-blind, placebo-controlled studies (Hollander and Pallanti, 2002
). However, one weakness of this approach is that approximately half of OCD patients do not respond to SRI treatment (Hollander and Pallanti, 2002
). A putative animal model of OCD that does not show sensitivity to chronic SRI treatment would then require validation based on other factors, such as epidemiological factors or neural circuitry. However, different subtypes of OCD may exhibit epidemiological characteristics that vary substantially from the population as a whole, and the precise neural circuitry involved in OCD is unknown. Thus, animal models of ‘treatment resistant’ OCD will be far more difficult to validate. Identification of endophenotypes for OCD will be critical for the development of current and novel animal models of OCD.
Genetic models of neuropsychiatric disorders using forward or reverse genetic approaches offer unique advantages and disadvantages. Forward genetic approaches begin with a phenotype of interest and attempt to identify the genetic variants that underlie the observed phenotypic variability. These studies focus on a genetically diverse population, such as a second-generation intercross (F2 cross) between two inbred strains, an outbred strain, or a wild population. QTL mapping strategies can then be applied to identify regions and ultimately specific genes that harbor variants that affect the trait of interest. Gene expression studies can also be used alone or in combination with QTL approaches to identify novel genes for the behavior of interest (Noctor et al., 2001
; Flint et al., 2005
; Palmer et al., 2006
). As forward genetic strategies do not make assumptions about which genes will influence the trait, they have the potential to identify completely novel genes. Major drawbacks include the substantial animal numbers, time, cost, and effort required, as well as difficulties associated with ultimately pinpointing a gene. Such approaches could be applied to the spontaneous barbering phenotype characterized by Garner et al. (2004)
or the stereotypic behavior characterized in deer mice by Korff et al. (2008)
. Reverse genetic approaches examine the effect of genetic manipulation (i.e. knockout or transgenic approaches) of a specific gene of interest. Reverse genetic approaches offer the advantage of better feasibility, relatively lower cost, and increased practicality; however, this approach does not allow for the identification of novel genes. Furthermore, attempting to model genetically complex neuropsychiatric disorders by altering the function of a single gene has been criticized. However, modeling only a specific aspect of a disorder increases the likelihood of a single gene playing a significant role in the phenotype. Furthermore, some human genetic studies of OCD suggest that single genes might contribute substantially to the risk for certain subtypes of OCD. In the end, forward and reverse genetic approaches should be seen as complimentary rather than mutually exclusive approaches, because genes initially identified by forward genetics can be specifically tested using the tools of reverse genetics. For example, the first mammalian circadian rhythm gene, ‘clock’, was discovered using forward genetic screens in mice (Vitaterna et al., 1994
) and was confirmed using a transgenic replacement strategy (Antoch et al., 1997
). Subsequent reverse genetic studies in mice have shown that clock modulates phenotypes relevant to bipolar disorder, which has been associated with abnormalities in the circadian system (Jones, 2001
; Roybal et al., 2007
In summary, a number of current genetic models of OCD show face and some predictive validity for OCD. Future work examining the effects of interventions with known consequences in OCD patients, such as chronic SRI treatment, in these mouse genetic models will be critical for their further development and validation. Furthermore, the identification of endophenotypes, or novel genes, treatments, or pathophysiological findings in OCD would greatly benefit the development of animal models for this disorder.