The Quest for Animal Models of Autism and Environment
A variety of animal models have been developed that aid in understanding the mechanisms that may induce one or several of the core features of autism (Ey et al. 2011; Hamilton et al. 2011; Tabuchi et al. 2007). In particular, transgenic and knock-in mouse lines with targeted anomalies in genes associated with autism and the development of a comprehensive set of rodent assays to assess social interaction, communication, and repetitive behaviors, have greatly enhanced our ability to test hypotheses about the causes of autism (Silverman et al. 2010). However, implementations of these tools toward understanding gene × environment interactions that promote impairments in the three key behavioral domains have lagged. The Shank3 (SH3/ankyrin domain gene 3) (Peca et al. 2011) and oxytocin knockout mice (Crawley et al. 2007) are examples of monogenetic insults that disrupt all three domains. However, because only a small proportion of autism cases result from complete loss of a single gene, knockout animal models may not be as useful as models that carry mutations that impart partial gain or loss of gene function.
Functional impairments as seen in the reeler mouse (Laviola et al. 2009) and Timothy syndrome mouse models (Bader et al. 2011) are more relevant to the multi-gene and environment model of autism risk. In a subsection of a paper describing the paradoxical effects of acetylcholinesterase [AChE; the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine (ACh)] in the reeler mouse, Laviola et al. (2006) describe the complexity of a gene × environment model whereupon exposure to chlorpyrifos restored behaviors to near normal that were initially impaired in the homozygous reeler mouse, and partially impaired in the heterozygous reeler mouse. It was shown that deficient cholinergic transmission in reeler mice could be restored by chlorpyrifos-mediated AChE inhibition. Subsequent studies found that perinatal estradiol levels influence the number of Purkinje cells and were regulated by reelin levels (Biamonte et al. 2009; Sigala et al. 2007). This sex × gene × environment interaction model serves more readily as a clue for further epidemiologic follow-up to understand autism etiology in humans (Halladay et al. 2009).
Several autism-associated genes are involved in Ca2+ signaling and regulation (Halladay et al. 2009; Pessah and Lein 2008). The Timothy syndrome mouse model of autism involves a single nucleotide mutation essential for proper voltage-dependent inactivation of the pore-forming subunit of the L-type calcium channel Cav1.2 (Splawski et al. 2004). Cav1.2 has been proposed to play direct roles in the development of synaptic plasticity (Morgan and Teyler 1999) and in gene translation and transcription (Dolmetsch 2003; Lenz and Avruch 2005; West et al. 2002).
Ca2+ signaling can be disrupted by polychlorinated biphenyls (PCBs, which are employed in a wide variety of industrial uses) (Pessah et al. 2010), the OC pesticides lindane and dieldrin (Heusinkveld and Westerink 2012), and several types of pyrethroid pesticides (Soderlund 2012). In a study comparing physiological effects of 11 pyrethroid compounds in rats, the type 2 pyrethroids strongly induced increased Ca2+ channel influx into the cell, whereas the type 1 pyrethroids did not (Breckenridge et al. 2009). It should be noted that these three exposure types induced calcium perturbations at levels below those described as having a toxic effect on the basis of primary mechanisms of action.
One could argue that mouse, rat, or zebrafish models may not demonstrate the core deficit that sets autism apart from other developmental disorders: a lack of social reciprocity. Recently, the prairie vole has been cited as a better model of autism due to its high degree of socialized behavior. For example, male prairie voles demonstrated social withdrawal after 10 days of dietary exposure to mercury, indicating a sex-specific effect of the exposure which induced a unique attribute of autism, social avoidance (Curtis et al. 2010).
Environ Health Perspect. 2012;120(7):944-951. © 2012 National Institute of Environmental Health Sciences