Protracted dendritic growth in the typically developing human amygdala and increased spine density in young ASD brains

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The amygdala, a cluster of nuclei in the medial temporal lobe, is implicated in a large number of neuropsychiatric disorders, including schizophrenia, depression, bipolar disorder, anxiety, and autism spectrum disorder (ASD; Schumann, Bauman, & Amaral, 2011; Kennedy & Adolphs, 2012). The amygdala functions as a danger and salience detector and, in turn, plays a key role in social and emotional regulation (Amaral, 2003; Adolphs, 2010). In typical development (TD), the amygdala continues to enlarge throughout childhood and into adolescence, a time period when growth of other brain regions (e.g., the hippocampus) has stabilized or are even decreasing in volume (e.g., the neocortex) (Giedd et al., 1996; Schumann et al., 2004; Ostby et al., 2009; Scott, Schumann, Goodlin‐Jones, & Amaral, 2009; Hunsaker, Scott, Bauman, Schumann, & Amaral, 2014; Raznahan et al., 2014). This unique feature of protracted growth could be essential for prolonged social and emotional development throughout the lifespan.
In ASD, a disorder characterized by deficits in social and communication skills, amygdala structure and function is of particular interest. Neuroimaging studies indicate that the amygdala growth trajectory is very different in ASD than in TD. Amygdala volume of children with ASD is significantly larger than in typically developing children (Sparks et al., 2002; Schumann et al., 2009; Mosconi et al., 2009; Kim et al., 2010; Nordahl et al., 2012). This relative overgrowth correlates with symptom severity, providing further evidence for the structure–function relationship of the amygdala in ASD (Munson et al., 2006; Mosconi et al., 2009; Schumann, Barnes, Lord, & Courchesne, 2009; Iidaka, Miyakoshi, Harada, & Nakai, 2012; Elison et al., 2013; Shen et al., 2016). However, the volume difference in ASD dissipates during adolescence as the amygdala continues to grow in TD (Schumann et al., 2004).
Magnetic resonance imaging (MRI) studies have provided insight into the growth trajectory of the amygdala at the macroscopic level; however, this approach does not have the resolution to investigate changes in individual nuclei or the underlying cellular differences responsible for these observations (Schumann & Nordahl, 2011). To date, few studies have evaluated postmortem human brains across the lifespan to determine the cellular underpinnings of amygdala growth in TD, nor how this is altered in ASD. In a previous study in our laboratory, we found evidence of accelerated cell loss in adult cases of ASD relative to TD cases, especially in the lateral nucleus (Schumann & Amaral, 2006; Morgan, Barger, Amaral, & Schumann, 2014). The lateral nucleus is the largest nucleus of the amygdala and is the main input structure that receives afferent signals from the cortex and hypothalamus. Information flows through the amygdala, either through the dorsal or ventral pathway, and exits via the central nucleus (Schumann, Vargas, & Lee, 2016). The lateral nucleus therefore plays the very important role of ‘gatekeeper’, establishing the initial threshold for which information is attended to via excitatory or inhibitory signaling.
Differences in neuronal morphology are strongly implicated in neurodevelopmental disorders since it is the fundamental feature of neuronal connectivity (Copf, 2016). Dendrites and the spines studded along their length are essential for maintaining neuronal communication, via finely tuned excitatory and inhibitory signaling (E/I balance) (Spruston, 2008; Gao & Penzes, 2015). In the present study, we quantify the morphology of neurons in the lateral nucleus of the amygdala across the lifespan from childhood to adulthood in TD and in ASD. We used a Golgi‐Kopsch staining protocol to first quantify morphological measures such as soma size, number of primary dendrites, and total dendritic length in the lateral nucleus of the amygdala. We then conducted a more fine‐grained analysis of spine density and maturity as an index of amygdala connectivity.

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