Neurodevelopmental Animal Models of Schizophrenia: Role in Novel Drug Discovery and Development

Abstract

Schizophrenia is a devastating mental illness that is associated with a lifetime of disability. For patients to successfully function in society, the amelioration of disease symptoms is imperative. The recently published results of two large antipsychotic clinical trials (e.g., CATIE, CUtLASS) clearly exemplified the limitations of currently available treatment options for schizophrenia, and further highlighted the critical need for novel drug discovery and development in this field. One of the biggest challenges in schizophrenia-related drug discovery is to find an appropriate animal model of the illness so that novel hypotheses can be tested at the basic science level. A number of pharmacological, genetic, and neurodevelopmental models have been introduced; however, none of these models has been rigorously evaluated for translational relevance or to satisfy requirements of “face,” “construct” and “predictive” validity. Given the apparent polygenic nature of schizophrenia and the limited translational significance of pharmacological models, neurodevelopmental models may offer the best chance of success. The purpose of this review is to provide a general overview of the various neurodevelopmental models of schizophrenia that have been introduced to date, and to summarize their behavioral and neurochemical phenotypes that may be useful from a drug discovery and development standpoint. While it may be that, in the final analysis, no single animal model will satisfy all the requirements necessary for drug discovery purposes, several of the models may be useful for modeling various phenomenological and pathophysiological components of schizophrenia that could be targeted independently with separate molecules or multi-target drugs.

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

“…1993), gene knockout models (Papaleo et al, 2012), pharmacological models (Amann et al, 2010), neurodevelopmental models (Wilson and Terry, 2010) and additional stress models (Oliver, 2011). Given the large numbers of rodent models currently used to mimic the phenotypes associated with SZ, it is becoming increasingly clear that validating these models will depend on the extent to which clinicians provide pertinent behavioral information and the accuracy with which behavioral testing of mice mimics the human endophenotype (Young et al, 2010).…”

Social interaction and social withdrawal in rodents as readouts for investigating the negative symptoms of schizophrenia

“…Demonstrating construct validity for animal models of schizophrenia is difficult as neurobiological substrates underlying the deficits associated with schizophrenia have not been clearly established (Wilson and Terry, 2010). However, the suggested neurobiology underling the deficits in social interaction behaviors in rodents are similar to pathophysiological features observed in schizophrenia.…”

“…Modeling symptoms of schizophrenia, in general and the negative symptoms, in particular, in animals is challenging because of the relatively poor understanding of the etiology and pathophysiology of the illness, as well as the human nature of the illness (Nestler and Hyman, 2010; Wilson and Terry, 2010; Van den Buuse et al, 2005). Nonetheless, efforts have been made to develop appropriate paradigms for various negative symptoms of schizophrenia including social withdrawal (Desbonnet et al, 2012; Ellenbroek and Cools, 2000; Neill et al, 2010).…”

Negative modulation of GABAA α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats

“…Enormous efforts have been made, not least by employing various pharmacological interventions, to mimic some of the clinically observed symptomatology of schizophrenia using rodents Wilson and Terry 2010;O'Tuathaigh and Waddington 2010). Two such strategies, the sub-chronic or early neonatal administration of phencyclidine (PCP), a N-methyl-D-aspartate receptor antagonist, induce a behavioural and neurobiological syndrome in rodents (upon cessation of treatment or in adulthood, respectively) that bears a remarkable similarity to some of the core symptoms observed in schizophrenic patients, including cognitive disruption (Jentsch and Roth 1999).…”