The amygdala has been implicated in a number of neurodevelopmental and psychiatric disorders, including autism spectrum disorder (ASD). This is likely because it is part of a system focused on detecting danger in the environment, processing cortical sensory input, and orchestrating subsequent responses. If this system becomes dysfunctional, inappropriate social behavior or anxiety may arise, as is observed in many, often debilitating, psychiatric disorders. Thus, treatment approaches may be facilitated by a precise understanding of the amygdala cellular composition and developmental trajectory that occurs across human lifespan. Considering impairments in social interaction and anxiety are key features of ASD, it is not surprising that the amygdala has been extensively implicated in ASD pathophysiology. The overarching objective of our research program is to reveal the cellular and molecular mechanisms underlying amygdala structure and function in typical human development and in ASD across the lifespan. In the first funding cycle of this research program, we discovered two phenomena through our studies of a large collection of human postmortem amygdala tissue samples. First, in neurotypical human brain development, the amygdala undergoes a substantial, protracted growth in both volume and in the number of mature neurons from youth well into adulthood. We hypothesize that this is attributable to a prolonged process of neuronal maturation in the basal and paralaminar nuclei, and that this protracted growth is critically important for normal social and emotional development. Second, in ASD brain development, the amygdala does not undergo the same age-related growth trajectory. Rather, the amygdala in ASD undergoes an aberrant, lifelong developmental time course that begins with premature volumetric enlargement and an excess number of mature neurons and synaptic spines in childhood. In fact, the number of mature neurons reaches adult levels by late childhood, suggesting that a preternatural neuronal maturation process is occurring in the amygdala basal and paralaminar nuclei. Dendrites of principal excitatory neurons in the amygdala of children with ASD also have an increase in spine density relative to neurotypical children, indicating altered neuronal synaptic communication. This increase is followed by a potentially degenerative cell loss as people with ASD age into adulthood. We have found that there is a steady decrease across age in the number of mature neurons in both the lateral and basal nucleus in adults with ASD relative to neurotypical adults. We hypothesize that hyperactivity and excitation in the amygdala, via an imbalance of excitatory to inhibitory (E:I) synaptic signaling, potentially contributes to anxiety, social impairments, and prospective neuron loss. We now move to the next phase of this research program, to identify specific neuronal properties and pathophysiological mechanisms that underlie the atypical amygdala cellular developmental trajectory in ASD that endures throughout the lifespan.

Public Health Relevance

There is extensive evidence implicating the amygdala in the pathophysiology of autism spectrum disorder (ASD) with ensuing anxiety and key socioemotional impairments. The overarching objective of our research program is to determine the cellular and molecular mechanisms underlying amygdala structure and function in typical human development and in ASD across lifespan. A more thorough understanding of the trajectory of amygdala cellular changes in ASD will pinpoint lifelong opportunities to treatment.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Developmental Brain Disorders Study Section (DBD)
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Gilotty, Lisa
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University of California Davis
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Lew, Caroline H; Groeniger, Kimberly M; Bellugi, Ursula et al. (2018) A postmortem stereological study of the amygdala in Williams syndrome. Brain Struct Funct 223:1897-1907
Weir, R K; Bauman, M D; Jacobs, B et al. (2018) Protracted dendritic growth in the typically developing human amygdala and increased spine density in young ASD brains. J Comp Neurol 526:262-274
Avino, Thomas A; Barger, Nicole; Vargas, Martha V et al. (2018) Neuron numbers increase in the human amygdala from birth to adulthood, but not in autism. Proc Natl Acad Sci U S A 115:3710-3715
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Stamova, Boryana; Ander, Bradley P; Barger, Nicole et al. (2015) Specific Regional and Age-Related Small Noncoding RNA Expression Patterns Within Superior Temporal Gyrus of Typical Human Brains Are Less Distinct in Autism Brains. J Child Neurol 30:1930-46
Barger, Nicole; Sheley, Matthew F; Schumann, Cynthia M (2015) Stereological study of pyramidal neurons in the human superior temporal gyrus from childhood to adulthood. J Comp Neurol 523:1054-72
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Liu, Xiao-Bo; Schumann, Cynthia M (2014) Optimization of electron microscopy for human brains with long-term fixation and fixed-frozen sections. Acta Neuropathol Commun 2:42

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