Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies

Abstract

Neurobehavioral disorders comprised of neurodegenerative, neurodevelopmental, and psychiatric disorders together represent leading causes of morbidity and mortality. Despite significant academic research and industry efforts to elucidate the disease mechanisms operative in these disorders and to develop mechanism-based therapies, our understanding remains incomplete and our access to tractable therapeutic interventions severely limited. The magnitude of these short-comings can be measured by the growing list of disappointing clinical trials based on initially promising compounds identified in genetic animal models. This review and commentary will explore why this may be so, focusing on the central role that genetic models of neurobehavioral disorders have come to occupy in current efforts to identify disease mechanisms and therapies. In particular, we will highlight the unique pitfalls and challenges that have hampered success in these models as compared to genetic models of non-neurological diseases as well as to symptom-based models of the early 20th century that led to the discovery of all major classes of psychoactive pharmaceutical compounds still used today. Using examples from specific genetic rodent models of human neurobehavioral disorders, we will highlight issues of reproducibility, construct validity, and translational relevance in the hopes that these examples will be instructive toward greater success in future endeavors. Lastly, we will champion a two-pronged approach toward identifying novel therapies for neurobehavioral disorders that makes greater use of the historically more successful symptom-based approaches in addition to more mechanism-based approaches.

Keywords: CNS disorders; behavioral genetics; behavioral neuroscience; preclinical; rodent models.

Figure 1

General questions to evaluate a model's utility. The questions proposed serve as a guide to establish the limits of validity and utility for characterization of behavioral phenotypes present in brain disorders. While they are also more broadly applicable to molecular and cellular phenotypes, they seek to identify obstacles within a model that prevent successful translation from the research lab to the clinic

Figure 2

Integration of “safeguards” in rodent model studies of brain disorders. In order to address barriers to translation such as those described in this review, we propose a series of suggestions in the development and use of rodent models, the design of preclinical studies that use them, and the clinical studies that are based upon successful preclinical work. Each of these “safeguards” helps to promote valid findings. Furthermore, if followed they will help to ensure that negative findings can still provide meaningful contributions to our understandings of the biology of the modeled disorders and the limits of our abilities to model them. While these safeguards were written with behavior in mind, they are also worthwhile considerations for models and diseases that involve molecular and histopathological components

Figure 3

Comparison of perspectives on modeling and intervention strategies for CNS disorders. (a) The “golden age” of animal‐based modeling and therapeutic screens emphasized interventions in normal animals that resulted in changes in behavior based on acute interventions. (b) Broadly speaking all genetic CNS disorders can be modeled using the paradigm shown. An underlying genetic deficit (possibly in combination with other genetic susceptibility loci and environmental exposures) gives rise to a pathological sequence of molecular changes (gene expression, protein expression) leading to changes in cellular function, neurotransmitter release, neurophysiological function, and ultimately affecting the highest levels of organismal function mediated by the CNS, which may include motor control, learning/memory, executive processing, emotional regulation, and social behavior