Criteria for validating mouse models of psychiatric diseases

Abstract

Animal models of human diseases are in widespread use for biomedical research. Mouse models with a mutation in a single gene or multiple genes are excellent research tools for understanding the role of a specific gene in the etiology of a human genetic disease. Ideally, the mouse phenotypes will recapitulate the human phenotypes exactly. However, exact matches are rare, particularly in mouse models of neuropsychiatric disorders. This article summarizes the current strategies for optimizing the validity of a mouse model of a human brain dysfunction. We address the common question raised by molecular geneticists and clinical researchers in psychiatry, "what is a 'good enough' mouse model"?

FIG. 1

Olfactory habituation/dishabituation. The mouse sniffs a cotton swab inserted into the cage lid. Time spent sniffing is scored with a stopwatch by a trained observer. A sequential series of cotton swabs are inserted and mice with normal olfaction will habituate to repeated exposures of the same odor and will dishabituate when presented with a new odor. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 2

Automated open field apparatus. Digiscan photocell-equipped automated open field. Locomotor activity is measured over time by a computer assisted analyzer. Beam breaks allow measurement of horizontal activity, total distance traveled, vertical activity, and time spent in the center of the open field. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 3

Rotarod. The Ugo Basile/Stoelting rotarod is a rotating cylinder covered with grooved plastic divided into sections to allow testing multiple mice at one time. Mice walk forward on the cylinder as it rotates at a constant speed or at speeds increasing from 4 to 40 rpm over a 5-min test session. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 4

Elevated plus maze. This is used to measure the conflict in the subject mouse between the natural tendency to avoid the open, narrow surface versus the tendency to explore a novel environment. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

FIG. 5

Sociability apparatus. The subject mouse is given a choice between exploring a habituated central start chamber or two side chambers, one containing a novel object, an empty wire cup or one containing an enclosed stranger mouse. Time spent in each chamber and entries into each chamber are automatically recorded by photocells located in the openings between the chambers. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]