A postmortem stereological study of the amygdala in Williams syndrome

Abstract

Perturbations to the amygdala have been observed in neurological disorders characterized by abnormalities in social behavior, such as autism and schizophrenia. Here, we quantitatively examined the amygdala in the postmortem human brains of male and female individuals diagnosed with Williams Syndrome (WS), a neurodevelopmental disorder caused by a well-defined deletion of ~ 26 genes, and accompanied by a consistent behavioral profile that includes profound hypersociability. Using unbiased stereological sampling, we estimated nucleus volume, number of neurons, neuron density, and neuron soma area in four major amygdaloid nuclei- the lateral nucleus, basal nucleus, accessory basal nucleus, and central nucleus- in a sample of five adult and two infant WS brains and seven age-, sex- and hemisphere-matched typically developing control (TD) brains. Boundaries of the four nuclei examined were drawn on Nissl-stained coronal sections as four separate regions of interest for data collection. We found that the lateral nucleus contains significantly more neurons in WS compared to TD. WS and TD do not demonstrate significant differences in neuron number in the basal, accessory basal, or central nuclei, and there are no significant differences between WS and TD in nuclei volume, neuron density, and neuron soma area in any of the four nuclei. A similarly designed study reported a decrease in lateral nucleus neuron number in autism, mirroring the opposing extremes of the two disorders in the social domain. These results suggest that the number of neurons in the lateral nucleus may contribute to pathological disturbances in amygdala function and sociobehavioral phenotype.

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

“…Furthermore, WS and ASD displayed quantitative changes in opposing directions compared to neurotypical controls. These findings contribute to a growing body of literature [7][8][9]18] in WS and ASD which demonstrate that both disorders display selective vulnerability of similar targets in the social brain, but in quantitatively opposing directions of change compared to healthy controls. This pattern parallels the dichotomous sociobehavioral phenotypes of the two disorders, suggesting that the microanatomical changes in neural structure of these regions may contribute to behavioral differences.…”

“…Adult data was collected by CL and infant data was collected by KG, after establishing inter-rater reliability with > 95% concordance. [9,14]). After boundaries on the SERT-ir stained sections were identified (Fig.…”

“…In contrast, autism spectrum disorder (ASD) is a common neurodevelopmental disorder (1/59 in the USA [4]) with a highly complex and heterogeneous genetic etiology and a behavioral phenotype characterized in part by reduced drive for social engagement and decreased attention/atypical processing of the eyes of others, an important social stimulus in humans [5,6]. Our previous studies in the postmortem brains of individuals with ASD [7] and WS [8,9] have demonstrated opposing patterns of difference compared to healthy controls in the number of neurons in the same key social brain areas, paralleling differences in social behavior. Together, these findings suggest that a direct comparison of these two disorders may offer a unique human model in which to examine changes in the brain that may contribute to the biological underpinnings of social behavior and, furthermore, may help elucidate critical neural targets for potential therapeutics in disorders accompanied by sociobehavioral difficulties.…”

“…In contrast, the central nucleus is critical to the autonomic loop of processing in the amygdala, as it lacks connectivity to association cortex, but receives heavy intra-amygdala projections, and serves as the major output nucleus of the amygdala to brain stem and hypothalamic regulatory centers [15][16][17]. In our postmortem studies of the amygdala in WS [9] and ASD [7,18], we found that the lateral nucleus was selectively vulnerable in both disorders, such that compared to NT, there was a significant increase in neuron number in the lateral nucleus in WS and a significant decrease in neuron number in the lateral nucleus in ASD. 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.…”

Serotonergic innervation of the human amygdala and evolutionary implications

“…Serotonergic axon density was quantified separately in the lateral, basal, accessory basal, and central nuclei, which are distinguished from each other by their connections with other brain areas, and have distinct boundaries that are consistently identified across individuals (Schumann & Amaral, ). For each SERT‐ir stained section examined, boundaries of the amygdaloid nuclei were first traced in Stereoinvestigator at 1x magnification, utilizing an adjacent Nissl‐stained section to ensure precision of boundaries as described in Lew et al () (Figure a). After boundaries were identified, the Space Balls probe was employed at ×100 magnification (1.4 numerical aperture, oil lens).…”