التهاب روده در مدل موش انواع اختلالات طیف اوتیسم

Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders characterized by impairments in communication, social interest and stereotypical behaviour. Dysfunction of the intestinal tract is reported in patients with ASD and implicated in the development and severity of ASD symptoms. However, more research is required to investigate the association of intestinal problems with ASD and the potential underlying mechanisms. The purpose of this study was to investigate comorbid symptoms of intestinal inflammation in a murine model of ASD induced by prenatal exposure to valproic acid (VPA). Pregnant BALB/c females were treated subcutaneously with 600 mg/kg VPA or phosphate buffered saline on gestational day 11. Offspring were housed with their mother until weaning on postnatal day 21 (P21). All pups were exposed to a social behaviour test on P28. Inflammatory correlates and activity of the serotonergic system were measured in brain and intestinal tissue. Here we demonstrate, in addition to reduced social behaviour and increased expression of neuroinflammatory markers in the brain, that VPA in utero- exposed male offspring showed epithelial cell loss and neutrophil infiltration in the intestinal tract. Furthermore, reduced levels of serotonin were not only observed the prefrontal cortex and amygdala of VPA in utero- exposed males, but also in the small intestine. Overall, we demonstrate that gender-specific inflammatory conditions are present in the small intestines of VPA in utero- exposed mice and are accompanied by a disturbed serotonergic system in the brain as well as in the intestinal tract.

Autism spectrum disorder (ASD) is a heterogeneous cluster of severe neurodevelopmental disorders. It is characterized by impairments in social interaction and communication and the presence of stereotyped behaviours (American-Psychiatric-Association, 2000). Although the aetiology of ASD is unknown, it is thought that ASD is a multifactorial disorder with a strong genetic component (Bailey et al., 1995 and Folstein and Rosen-Sheidley, 2001). A variety of environmental factors is suggested to contribute to ASD development. For example, prenatal exposure to teratogens has been shown to be a significant risk factor for ASD (Dufour-Rainfray et al., 2011). Indeed, maternal use of the anticonvulsant valproic acid (VPA) is associated with the development of ASD in the offspring (Christensen et al., 2013, Moore et al., 2000 and Rasalam et al., 2005). The mechanism for VPA-induced symptoms of ASD is still unclear, but several pathways have been proposed. These include attenuation of folic acid metabolism, inhibition of histone deacetylases and increased oxidative stress (Ornoy, 2009). In search of underlying mechanisms, animal models of VPA-induced autism-like behaviours have been established in rats and mice. In a well-characterized murine model, VPA in utero- exposed mice exhibit developmental and behavioural deficits comparable to those observed in ASD patients, including deficits in social behaviour ( Kataoka et al., 2013 and Roullet et al., 2010), stereotyped behaviour ( Wagner et al., 2006), anxiety and impairments in cognition ( Kataoka et al., 2013). Furthermore, observations were more prominent in male offspring compared to female offspring ( Kataoka et al., 2013 and Kim et al., 2013), which reflects the human situation where a marked male preponderance is observed in ASD patients ( Fombonne, 2005 and Lord et al., 1982). Disturbances in the immune system are repeatedly reported in various organs of ASD patients. Since ASD is primarily a disorder of the central nervous system, the brain is a major target for immunological research. In post-mortem brains of patients with ASD, marked activation of astroglia and microglia is observed when compared to controls (Fatemi et al., 2008, Laurence and Fatemi, 2005, Morgan et al., 2010, Tetreault et al., 2012 and Vargas et al., 2005), indicative of neuroinflammation. Enhanced activation of neuroglia was also observed in various murine models of autism (Derecki et al., 2012, Ratnayake et al., 2012 and Yuskaitis et al., 2010). In addition, enhanced levels of a wide range of cytokines and chemokines were found in the brain (Li et al., 2009) and in the cerebrospinal fluid (Vargas et al., 2005) of autistic children, compared to healthy children. This supports the presence of neuroinflammatory conditions in the brain of ASD patients. Peripheral immune abnormalities in autistic individuals have also been reported, including differential monocyte responses to in vitro stimulation ( Jyonouchi et al., 2005 and Molloy et al., 2006), dysfunctional natural killer (NK) cells ( Enstrom et al., 2009 and Vojdani et al., 2008) and altered serum levels of immunoglobulins ( Croonenberghs et al., 2002, Heuer et al., 2008 and Lucarelli et al., 1995), cytokines ( Ashwood et al., 2011a, Manzardo et al., 2012 and Singh, 1996) and chemokines ( Ashwood et al., 2011b). Immune disturbances have also been observed in the gastrointestinal tract of ASD patients. The presence of gastrointestinal problems in these patients is repeatedly reported in literature and include chronic constipation, diarrhoea and abdominal pain (de Theije et al., 2011). These symptoms have been attributed to changes in gut microflora (Desbonnet et al., 2013 and Louis, 2012), increased intestinal permeability (de Magistris et al., 2010) and intestinal inflammation (Ashwood et al., 2003). Although evidence is emerging, there is still much debate about the presence of gastrointestinal disturbances in ASD. Indeed, the reported prevalence of gastrointestinal symptoms ranges from 9% to 91%, an immense range probably due to varying interpretations of gastrointestinal problems and inability of ASD patients to express their discomfort (Coury et al., 2012). Moreover, diagnosis of ASD is based on behavioural observations, gathering a heterogeneous cluster of patients with different aetiologies. Deficits in the intestinal tract could therefore be specific for a subgroup of ASD patients. Since gastrointestinal deficits have been suggested to contribute to the development or severity of autistic behaviour (Adams et al., 2011), a considerable number of ASD patients is on a specific diet to improve gastrointestinal function and behaviour (Levy and Hyman, 2003). Nevertheless, more research is required to clarify the importance of gastrointestinal disturbances in ASD patients and to understand possible underlying mechanisms. The aim of this study was to investigate the effects of prenatal exposure to VPA on immune activation in the gut and brain. We also investigated the serotonergic system in the gut and brain as a putative neuroimmune modulator and a potential mechanism underlying the effects of prenatal VPA exposure on behaviour and intestinal phenotype.