ASD is a socially debilitating condition with an extraordinarily high rate of heritability. The prominent role of genetics in ASD has prompted scientists to search for genetic candidates for the disorder, a process that often involves the development of genetically engineered mice. For example, if a genetic mutation is identified through human studies as a possible candidate for ASD, researchers can develop an analogous mutation in the mouse genome. Mouse knockout models, in which genetically modified stem cells are strategically injected into pregnant females, can be used to generate a desired mutant strain of mice.
Once the genetically engineered strain of mouse has been generated, the next step is behavioral phenotyping, a form of behavioral profiling to determine whether the new mouse strain is a “match” for the human disorder of interest. A challenge with ASD is that no definitive biological cause has been identified, so researchers have emphasized behavior (Silverman, Yang, Lord, & Crawley, 2010). According to the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), ASD is characterized by (1) “persistent deficits in social communication and social interaction across multiple contexts” and (2) “restricted, repetitive patterns of behavior, interests, or activities” (American Psychiatric Association, 2013). With these behavioral targets in mind, several strains of mice have been engineered, each meeting the criteria described in the DSM-5 with varying success.
One mouse model that shows promise as a model of ASD is the black and tan brachyuric (BTBR) mouse strain (Clee, Nadler, & Attie, 2005). Compared with a more standard mouse strain, the BTBR strain of mice exhibits compromised social interactions such as diminished reciprocal social interactions, delayed approaches to mouse peers, decreased evidence of social communication, and repetitive self-grooming (Scattoni, Gandhy, Ricceri, & Crawley, 2008). In a study conducted by Jacqueline Crawley and her colleagues at the National Institute of Mental Health, the BTBR and control mice were placed, one at a time, in an apparatus with three chambers. One chamber had a mouse placed in a small enclosure, another had the enclosure object with no mouse, and the third compartment was empty. The question was simple: where would each mouse prefer to spend time, with another mouse, with an object, or in an empty chamber? The control mice spent more time with the mouse, whereas the BTBR mice spent more time with the object. Each control mouse sniffed the mouse in the apparatus, whereas each BTBR mouse showed no preference, sniffing the object as much as it did the other mouse (Silverman et al., 2010).
With the identification of a potential animal model, scientists begin trying to identify biological correlates of the targeted symptoms of ASD. When neuroscientists examined the mice brains, they found a surprise. These mice lack a corpus callosum, an effect not characteristic of human ASD patients—although smaller volumes of the corpus callosum have been observed in ASD patients compared with healthy controls (Vidal et al., 2006). Other neurological differences between the BTBR and standard mice include a smaller hippocampus and greater number of unmyelinated axons in the BTBR strain (Stephenson et al., 2011). Do these neuroanatomical differences invalidate this seemingly valid model of autism? Although the results are preliminary, compromised hippocampal neurons and decreased myelination have been observed in human cases (Raymond, Bauman, & Kemper, 1996; Zikopoulis & Barbas, 2010).
Although this animal model is far from perfect, it has helped scientists to explore the symptoms of ASD in new ways. After learning throughout this chapter about the dramatic changes that the brain experiences during development, we can see how certain missteps may occur along the developmental path. Early-stage research on ASD suggests that these neural missteps can have far-reaching effects. Once scientists learn more about the cause or causes of ASD in humans, they may be able to create an even better animal model of ASD for laboratory studies. Scientists will continue to learn as much as possible about the developing brain to identify specific mechanisms of functional impairments associated with the broad spectrum of neurodevelopmental disorders.