Age-Related Decline in Neuron Number in the Amygdala in ASD

Background: The amygdala undergoes aberrant development and function across the lifespan in most individuals with an autism spectrum disorder (ASD). Given its role in mediating social and emotional appraisal and response, it has long been the focus of research on ASD pathophysiology. From MRI studies, we know that the amygdala is increased in size in the majority of children with ASD, however this size difference does not persist into adulthood. In contrast, in histological analyses, we have previously found that neuron numbers in the amygdala are reduced in adults that had ASD during life. Reduced neuron numbers were most evident in the lateral nucleus, a major input region for sensory and cognitive information into the amygdala. However, the cellular neuropathology underlying aberrant amygdala development from childhood to adulthood remains relatively unexplored in ASD.

Objectives: Given previous findings of decreased neuron numbers in adults with autism, this study sought to determine if there are age-related changes in the number of neurons in the amygdala of typical and ASD brains. Because the amygdala is structurally and connectively heterogeneous and not all of its nuclei evidence reduced neuron number in adults, we used stereological methods to quantify age-related cellular variation in four individual amygdaloid nuclei: the lateral, basal, accessory basal, and central nuclei.

Methods: The optical fractionator technique was used to estimate neuron number in four amygdala nuclei (lateral, basal, accessory basal, and central) on Nissl-stained coronal sections of ASD and typical control postmortem brains ranging from 2-44 years of age. To assess age-related variation, linear regressions of neuron number and age were performed for each nucleus for each diagnostic group.

Results: In controls, there was no significant relationship of age and neuron number in any of the nuclei analyzed (p > 0.05). In contrast, in the ASD cases, lateral (p = 0.02) and central (p = 0.03) nucleus neuron numbers showed significant negative linear relationships with age. No significant trends were observed in the other amygdala nuclei (p > 0.20) in the ASD cases. 

Conclusions:  Our findings indicate that neurons in the amygdala may be undergoing developmental decline in ASD cases, compared to typically developing individuals. Furthermore, they suggest that the neuropathology of the amygdala observed in adults with ASD may be the product of events occurring throughout the post-natal time period of development. Assessing autistic neuropathology across age groups can help to better characterize potential developmental mechanisms underlying significant variation in the brains of adults with ASD as well as to identify sensitive neurodevelopmental periods to better inform treatment programs