Abstract
BackgroundWilliams 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.MethodsWe 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.ResultsWe 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.LimitationsThis 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.ConclusionsDifferential 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.
Highlights
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
Differential alterations to serotonergic innervation of the amygdala may contribute to differences in sociobehavioral phenotype in WS and ASD
In the present study, we found trends of a slight increase in mean serotonin transporter (SERT)-ir axon density in ASD compared to NT and a decrease in mean SERT immunoreactive (SERT-ir) axon density in WS compared to NT (Tables 2, 3, and 4; Fig. 3)
Summary
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. Neuroimaging studies have demonstrated structural and functional abnormalities of the amygdala in many neurological disorders that are accompanied by atypical social behavior, including in the WS and ASD amygdala [10,11,12,13]. The lateral, basal, and accessory basal nuclei are thought be involved in cognitive processing given the significant bidirectional connectivity to association areas in the frontal and temporal lobes [15,16,17]. The lateral nucleus is the primary site of cortical input into the amygdala and an important region for cognitive processing of external stimuli, so these targeted alterations, in opposing directions of change, may contribute to differential atypical processing of social stimuli in WS and ASD
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