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    • Studies focusing on typically developing individuals Bertoli

    2018-11-07

    Studies focusing on typically developing individuals (Bertolino et al., 2005; Canli et al., 2005; Hariri et al., 2005; Pezawas et al., 2005; Wiggins et al., 2014b) link variation in amygdala functioning and amygdala-sACC connectivity to serotonin transporter-linked polymorphic region (5-HTTLPR) genotypes. If 5-HTTLPR genotype affects amygdala functioning, amygdala-sACC connectivity, and socioemotional behavior across diagnoses, it may also affect connectivity, and as a possible consequence, variation in amygdala activity and social behavior in ASD. 5-HTTLPR is a functional polymorphism found in the promoter region of the gene that encodes the serotonin transporter (SERT), a protein that modulates serotonin function (Hu et al., 2006). The 5-HTTLPR polymorphism directly affects SERT expression and consequently serotonin function in that individuals with the short variant (S) produce less SERT mRNA and protein than individuals with the long (L) variant, thus creating increased levels of serotonin in the synaptic cleft. TD individuals who are carriers of 5-HTTLPR short (S) OTX-015 exhibit increased anxiety related traits (Canli and Lesch, 2007), depressive symptoms (Caspi et al., 2003), as well decreased functional connectivity between the amygdala and the sACC when looking at fearful faces (Pezawas et al., 2005). Whereas studies have found inconclusive evidence of an association between 5-HTTLPR and susceptibility to ASD (e.g. Cook and Leventhal, 1996; Devlin et al., 2005; Zhong et al., 1999; Ramoz et al., 2006), various reports highlight the effect of genotype on the severity of social dysfunction in ASD, which may be related to amygdala functioning and its connectivity with the sACC. For example, Tordjman et al. (2001) found evidence of increased severity in the Combined Social and Communication domain subset of the Autism Diagnostic Interview- Revised (ADI-R; Lord et al., 1994) in participants with the S allele compared to those homozygous for the L allele. Similarly, Brune et al. (2006) found an effect of 5-HTTLPR genotype on non-verbal social interaction severity where participants with S/S or S/L genotypes displayed more severity compared to those with the L/L genotype; individuals with L/L genotypes exhibited increased severity of restricted and repetitive behaviors. There are reports however, pointing to more severe social deficits in participants homozygous for the L allele (Gadow et al., 2013), which contradicts previous data. In sum, 5-HTTLPR seems to affect aspects of social dysfunction in ASD, despite a lack of association between 5-HTTLPR and susceptibility to ASD. 5-HTTLPR can be subdivided into further allelic variants (Nakamura et al., 2000). Short (S) alleles and long (L) alleles with genotypes that contain the G (i.e. SG and LG) variants are associated with decreased SERT expression compared to individuals with long alleles and genotypes that contain the A variant (i.e. LA; Hu et al., 2006). Recent studies have grouped S/S, S/LG and LG/LG genotypes as low expressing genotypes of the 5-HTTLPR polymorphism (Gadow et al., 2013; Wiggins et al. 2014a,b). Wiggins et al. (2013) examined the influence of 5-HTTLPR on resting connectivity in ASD and found that youth with the low expressing genotypes exhibited stronger connectivity in the default network than higher expressing genotype groups, whereas the opposite was true for the TD group. In addition, youth with low expressing genotypes show decreased amygdala habituation (i.e., more sustained activation over time) in response to emotional faces (Wiggins et al., 2014a).
    Method
    Results
    Discussion If replicated in a larger sample, the relationship between lower levels of social dysfunction and higher connectivity in participants with ASD and higher expressing genotypes points to the possibility that connectivity between the amygdala and the sACC, at rates comparable to TD individuals, may help modulate social function when individuals view happy faces (e.g. positive social interactions). This possibility is supported by studies showing that the areas of the ventral prefrontal cortex modulate amygdala activity (Milad and Quirk, 2012; Ray and Zald, 2012), and that greater connectivity between the amygdala and the sACC is related to greater amygdala habituation to sad faces in controls (Swartz et al., 2013). Contrastingly, individuals with ASD and low expressing genotypes showed hyperconnectivity at all levels of social dysfunction. We speculate that functional connectivity at abnormally high rates may impede a modulatory relationship between connectivity and social dysfunction.