Serotonergic innervation of the amygdala is increased in autism spectrum disorder and decreased in Williams syndrome

Abstract

Background: Williams syndrome (WS) and autism spectrum disorder (ASD) are neurodevelopmental disorders that demonstrate overlapping genetic associations, dichotomous sociobehavioral phenotypes, and dichotomous pathological differences in neuronal distribution in key social brain areas, including the prefrontal cortex and the amygdala. The serotonergic system is critical to many processes underlying neurodevelopment and is additionally an important neuromodulator associated with behavioral variation. The amygdala is heavily innervated by serotonergic projections, suggesting that the serotonergic system is a significant mediator of neuronal activity. Disruptions to the serotonergic system, and atypical structure and function of the amygdala, are implicated in both WS and ASD. Methods: We quantified the serotonergic axon density in the four major subdivisions of the amygdala in the postmortem brains of individuals diagnosed with ASD and WS and neurotypical (NT) brains. Results: We found opposing directions of change in serotonergic innervation in the two disorders, with ASD displaying an increase in serotonergic axons compared to NT and WS displaying a decrease. Significant differences (p < 0.05) were observed between WS and ASD data sets across multiple amygdala nuclei. Limitations: This study is limited by the availability of human postmortem tissue. Small sample size is an unavoidable limitation of most postmortem human brain research and particularly postmortem research in rare disorders. Conclusions: Differential alterations to serotonergic innervation of the amygdala may contribute to differences in sociobehavioral phenotype in WS and ASD. These findings will inform future work identifying targets for future therapeutics in these and other disorders characterized by atypical social behavior.

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model

“…We measured SERT binding in several brain regions (Figure 4(A)). We focused on amygdalar regions relevant to the human postmortem studies 63 and fear conditioning phenotypes, 64 assessing BLA, central amygdala (CeA) and LA regions independently based on findings that they differ in the amount of serotonergic innervation in some species 65 . We then included other areas where SERT has been implicated in behaviors relevant to the WS phenotype, patient findings and knowledge of 5HT biology.…”

Comparison of Adaptive Functioning in Children with Williams Beuren Syndrome and Autism Spectrum Disorder: A Cross‐Syndrome Study

“…Although children with WBS appear to be hypersociable when compared to ASD children, both populations share deficits in some socio‐communicative skills, such as, in preschool age, difficulty in shared attention, showing or giving objects and, in school age, difficulty in social relationships comprehension, pragmatic use of language, and emotion's recognition [Vivanti et al, 2018]. Reconsidering phenotypes similarities between WBS and ASD has presumably resulted in a renewed interest in cross‐syndrome studies on phenotypical, behavioral, biological and clinical comparison [Glod, Riby, & Rodgers, 2019; Ashworth, Palikara, & Van Herwegen, 2019; Hamner et al, 2019; Baptista et al, 2019; Lew et al, 2020; Ridley, Riby, & Leekam, 2020].…”

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model

“…61 More recently, Lew et al (2020) compared serotonergic innervation in the amygdala between autism and WS in human postmortem samples, concluding that there is decreased innervation in WS brains compared to neurotypical brains. 62 Therefore, we focused on the SERT, as it should provide a measure of serotonergic innervation to different structures.…”

“…We measured SERT binding in several brain regions. We focused on amygdalar regions relevant to the human postmortem studies 62 and fear conditioning phenotypes, 63 assessing BLA, central amygdala (CeA), and LA regions independently based on findings that they differ in the amount of serotonergic innervation in some species. 64 We then included other areas where SERT has been implicated in behaviors relevant to the WS phenotype, patient findings, and knowledge of 5HT biology.…”