پروفایل های التهابی در ماوس BTBR : چگونه آنها به اختلالات طیف اوتیسم مربوط است؟

Autism spectrum disorders (ASD) are a group of disorders characterized by core behavioral features including stereotyped interests, repetitive behaviors and impairments in communication and social interaction. In addition, widespread changes in the immune systems of individuals with ASD have been identified, in particular increased evidence of inflammation in the periphery and central nervous system. While the etiology of these disorders remains unclear, it appears that multiple gene and environmental factors are involved. The need for animal models paralleling the behavioral and immunological features of ASD is paramount to better understand the link between immune system dysregulation and behavioral deficits observed in these disorders. As such, the asocial BTBR mouse strain displays both ASD relevant behaviors and persistent immune dysregulation, providing a model system that has and continues to be instructive in understanding the complex nature of ASD.

Autism spectrum disorders are a group of neurodevelopmental disorders characterized by restricted interests, repetitive behaviors and impairments in communication and social interaction. Currently 1 in 88 children have been identified as having ASD (CDC, 2012). Despite the high incidence of ASD, the etiology and pathogenesis remain poorly understood. Numerous published findings have identified widespread changes in the immune systems of individuals with ASD both at the systemic and cellular levels (Ashwood et al., 2006). These immune dysfunctions are associated with impairments in core features of ASD as well as aberrant behaviors, decreased adaptability and impaired cognition (Ashwood et al., 2011a, Ashwood et al., 2011b and Onore et al., 2012). In individuals with ASD, several lines of evidence point to ongoing inflammation both within the brain (Li et al., 2009, Morgan et al., 2010 and Vargas et al., 2005) and in the periphery (Ashwood et al., 2011a and Hashimoto et al., 2011). Work by Vargas et al. demonstrated that in postmortem brains from subjects with ASD there were signs of increased pro-inflammatory cytokines including interleukin (IL)-1β, IL-6, IL-12(p40) and TNFα (Vargas et al., 2005). Moreover, microglia from subjects with ASD display a more activated phenotype in postmortem brain (Morgan et al., 2010) and by PET scan (Suzuki et al., 2013). In addition to immune activation within CNS, circulating levels of cytokines exhibit a profile reminiscent of a proinflammatory immune profile with increased IL-1β, IL-6 and IL-12(p40) production (Ashwood et al., 2011a, Hashimoto et al., 2011, Ricci et al., 2013 and Singh, 1996). Increased activation of circulating monocyte cells in the periphery following stimulation with Toll-like receptor (TLR) ligands has also been observed, including changes in gene expression, increased HLA-DR cell surface expression and the release of pro-inflammatory cytokines IL-1β and IL-6 (Enstrom et al., 2010, Jyonouchi et al., 2008, Jyonouchi et al., 2011 and Jyonouchi et al., 2001). Both the circulating levels of these pro-inflammatory cytokines and the degree of monocyte activation are associated with more impaired behaviors in children with ASD (Ashwood et al., 2011a, Enstrom et al., 2010 and Onore et al., 2012). These findings notwithstanding, many of the links between ASD and immune system dysregulation are drawn from associative studies that pose compelling correlations between neurodevelopmental disorders and immune dysfunction. However, limitations in experimental design and the myriad of uncontrolled variability, as a result of ethical boundaries placed on human research, requires the use of animal models to effectively link causality to these patterns of association. Rodent models of human conditions enable scientists to directly test hypotheses generated from evidence drawn from clinical populations. The development of an effective animal model requires extensive investigation into the biological and behavioral pathologies that contribute to the face, construct, and predictive validity of a translational model. These validity measures are crucial for evaluating the relevance of a model for understanding the human condition. For the study of ASD and its associations with immune system dysregulation, researchers have identified a mouse strain, the BTBR mouse, that has strong validity for evaluating the neuro-immunological contributions to ASD-like behaviors. BTBR mice were derived from an inbred strain carrying the at (nonagouti; black and tan) and wildtype T (brachyury) mutations that were crossed with mice with the tufted (Itpr3tf) allele (http://jaxmice.jax.org/strain/002282.html). As part of the Mouse Phenome Project (MPP), BTBR mice were characterized and found to have neuroanatomical abnormalities such as a hereditary loss of corpus callosum (Wahlsten et al., 2003). However, it was not until work by Moy et al., who characterized the BTBR mice as exhibiting behaviors that had strong face validity to ASD, that the BTBR mouse was brought to the attention of the neurodevelopmental research community (Moy et al., 2007). More recent work by Heo et al. described the immune system of the BTBR mouse as having a number of immunological abnormalities consistent with increased immune activation (Heo et al., 2011). In light of the mounting evidence of immune dysfunction in ASD coupled to the behavioral abnormalities, the BTBR mouse makes for an interesting target to research mechanisms of asocial behaviors as they relate to immune dysfunction (Reviewed in Onore et al., 2012) and may help to better understand the complex nature of ASD.

The BTBR mouse model has many behavioral and immunological features relevant to ASD. Investigation into the immune abnormalities of this inbred strain may help to understand the role immune dysregulation plays in behavioral responses. The inflammatory environment created by M1 macrophages in these animals parallels many of the immunological finding in human subjects with ASD. A skewed innate immune response seems to increase behavioral deficits in both the social and repetitive domains. These deficits appear to result at least in part from maternal immune dysfunction and its effect on the developing fetus. Experiments to further exacerbate the maternal immune environment results in increased impairments in BTBR animals, and the transfer of BTBR embryos into C57BL/6J dams abrogates much of the behavioral phenotype present. However, repetitive behaviors remain increased in BTBR animals even when they develop in a C57BL/6J dam, suggesting that several additional factors contribute to the BTBR phenotype than simply the maternal environment. Indeed, inflammatory markers in adult BTBR animals correlate with increased repetitive behaviors, suggesting that persistent immune dysregulation in juvenile and adult animals also contributes to the behavioral phenotype in BTBR mice. Although not fully understood, work in other immune behavioral models would suggest that peripheral immune dysfunction can work in two ways: peripheral cytokines/chemokines can enter into the CNS at low or high levels during disease states, where they can directly affect neuronal development and function; or alternatively, these cytokines/chemokines can activate perivascular macrophages or microglia which in turn produce downstream factors which can alter neuronal function (Fig. 1). Similarly, as alteration in mitochondrial function have been observed in the MIA mouse model (Giulivi et al., 2013), mitochondrial functions should be investigated in the BTBR mouse as well, given that these changes could lead to increased oxidative stress and neuroinflammation (James et al., 2004). Future work into the immune dysfunction of BTBR animals should help to elucidate their role in aberrant behavior and neurodevelopment. Full-size image (51 K)