Autism Spectrum Disorder (ASD) is characterized by three classes of symptoms: 1) absent or reduced verbal and nonverbal social communication, 2) low levels of social approach and reduced reciprocal interpersonal interaction, 3) stereotyped or repetitive behaviors, narrow interests, and resistance to change in routines or habits. In the US, ASD occurs with an incidence of 1 in 166 children, and reflects abnormalities in prenatal and postnatal brain development. More specifically, growth abnormalities in the cerebellum, amygdala, and hippocampus have been reported in children with ASD, and overall brain size in ASD exceeds the normal average by about 10%. At the neuropathological level, postmortem analyses of ASD brains have revealed decreased numbers of Purkinje neurons in the cerebellum, misoriented pyramidal neurons in the cerebral cortex, and cell number abnormalities in the deep cerebellar nuclei and inferior olive (DiCicco-Bloom et al., 2006).
Mice are highly social animals with significant capacities for spatial learning and novelty-seeking behavior. Many of these behaviors, in particular those relevant to the ASD phenotype, can be assayed readily in the laboratory. In addition to the opportunities for transgenic manipulations and conditional targeted mutagenesis in mice, there is a wealth of inbred strains available for comparative behavioral studies, with potential for microarray analyses and identification of quantitative trait loci. As part of the Mouse Phenome Project, Wahlsten and colleagues (2003) expanded their earlier data on rotarod performance in mouse strain BTBR T/t+ tf/tf (BTBR), to compare brain size and commissure anatomy in 21 different inbred strains. Specifically, they consistently found severe deficits in the hippocampal commissure and corpus callosum, both of which are large collections of nerve fibers (axons) that cross the midline between the two cerebral hemispheres.
MRI studies of individuals with ASD have revealed reduced or absent (agenesis) corpus callosum, and the paper (Moy et al., 2007) under discussion here shows that BTBR mice, in addition to the anatomical similarities in forebrain commissures, share some behavioral characteristics with autistic humans. In an NIH Public Access manuscript, these researchers report on the behavior of ten different inbred strains, as monitored in tasks that are relevant to the characteristics of ASD. To control for possible differences in physical or physiological traits that might affect the ability of a mouse to perform the social and reversal tasks in the study, the investigators first examined general health and strength, home cage behaviors (e.g. nest-building), olfactory ability, coordination, and activity in an open field. Male mice from ten inbred strains were then assessed for performance in two basic types of behavioral tests: social approach, and resistance to reverse a learned pattern of behavior.
The social behavior testing started with an analysis of sociability, through measurement of the time the test mouse spent approaching and sniffing a wire cage containing an unfamiliar mouse. This test continued with a measurement of preference for social novelty, through quantitating time spent in an alternative chamber containing a new, unfamiliar mouse (restricted in a small wire cage as before), as compared to time spent in the chamber containing the now-familiar mouse. Resistance to change was measured by two “reversal learning” tasks. The T-maze task is appetite-motivated, and mice are trained to enter one arm of a T-maze by reward with a food pellet; mice that acquired the training criterion were then tested for reversal learning, after the food reward location was switched to the opposite arm of the maze. The Morris water maze, in which a submerged platform in a swimming pool must be located using visual cues in the surrounding room (usually on the walls) is a classic test for spatial learning in mice and rats. In this study, mice learned to swim to a visible escape platform, and reversal learning was tested using the submerged platforms. In short, the mouse sociability tests address the low or aberrant interpersonal interaction in ASD, while the T-maze and Morris water maze address the cognitive inflexibility characteristic of this disorder.
In their discussion, Moy and colleagues assessed the performance of each of the inbred mouse strains in the behavioral tasks, and carefully considered alternative explanations for the differences. Some strains, such as C3H/HeJ and FVB/NJ, become blind at an early age due to retinal degeneration, while others, such as the A/J strain, have motor deficits due to a muscular dystrophy-like gene. Differences in anxiety levels, exploratory activities, and learning abilities, which might confound sociability or reversal learning measurements, also had to be considered. At the end of the day(s!), the BTBR strain is perhaps the most promising, of the inbred strains tested, as a mouse model for at least two of the behavioral characteristics associated with ASD. First, these mice exhibited significantly lower sociability scores, in terms both of time spent in the chamber containing a new stranger mouse (as compared to an inanimate novel object), and of preference for social novelty. Second, although the BTBR mice performed normally in the control tests for anxiety and open field activity, they had low scores in the reversal learning tasks, for both the T-maze and Morris water maze. However, as a final note of caution, the authors stated that it is unlikely that any one mouse model will replicate all aspects of the complex ASD phenotype. Over the next few weeks, I’ll discuss papers that describe other autism mouse models.
DiCicco-Bloom, E., Lord, C., Zwaigenbaum, L., Courchesne, E., Dager, S.R., Schmitz, C., Schultz, R.T., Crawley, J., Young, L.J. (2006). The developmental neurobiology of autism spectrum disorder. J. Neurosci. 26, 6897-6906.
*Moy, S.S., Nadler, J.J., Young, N.B., Perez, A., et al. (2007). Mouse behavioral tasks relevant to autism: phenotypes of ten inbred strains. Behav. Brain Res. 176(1), 4-20.
Wahlsten, D., Metten, P., Crabbe, J.C. (2003). Survey of 21 inbred mouse strains in two laboratories reveals that BTBR T/+ tf/tf has severely reduced hippocampal commissures and absent corpus callosum. Brain Res. 971, 47-54.
* primary peer-reviewed paper discussed in this post, the second in a Weekend Series on Animal Disease Models
MOY, S., NADLER, J., YOUNG, N., PEREZ, A., HOLLOWAY, L., BARBARO, R., BARBARO, J., WILSON, L., THREADGILL, D., LAUDER, J. (2007). Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains. Behavioural Brain Research, 176(1), 4-20. DOI: 10.1016/j.bbr.2006.07.030