20493
Neuropathology of Maternal Immune Activation in a Nonhuman Primate Model
Activation of the maternal immune system during pregnancy increases the risk of offspring developing neurodevelopmental disorders including autism spectrum disorder (ASD). Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavior development in offspring. Findings include aberrant neuron morphology in the medial pre-frontal cortex and decreased parvalbumin expression in the ventral hippocampus (Li et al., 2014; Giovanoli et al., 2014). We have recently extended the model to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop aberrant behaviors relevant to the core symptomatology of ASD (Bauman et al., 2014).
Objectives:
The goal of this study was to comprehensively characterize markers of brain pathology and potential aberrant immune response in MIA-treated and control offspring, including neuronal dendritic arborization, spine density, cell morphology, and immunohistochemistry.
Methods:
Tissue was processed from 8 animals (4 MIA-treated, 4 control). Blocks of frontal cortex were first stained using the Golgi-Cox method to evaluate dendritic morphology. 150μm coronal sections were cut on a sliding microtome and mounted. The morphology of pyramidal cells in layer III of the dorsolateral pre-frontal cortex (BA46) cortex was recorded and analyzed using Neurolucida software. 10 neurons per case were traced in their entirety (length and branching of apical and basal dendrites and spine density were measured). In addition, a more in-depth analysis of the apical dendrite was completed for 30 neurons/case by quantifying diameter, spine density and number of branches in a 30μm section located 100±10μm from the soma. For the initial immunohistochemical studies, we qualitatively and quantitatively characterized parvalbumin positive neurons in the hippocampal formation. 30μm thick sections were processed with DAB visualization (Parvalbumin primary antibody 1:5000, Swant, Switzerland).
Results:
While no significant group differences were found from the initial 10 neurons, significant differences were detected in the more in depth analysis of apical dendrite morphology. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter (2.28μm vs. 2.76μm; Z=2.31, P<0.05) and had a greater number of oblique dendrites (4.74 vs. 3.53; Z=2.14, P<0.05). Preliminary analyses did not indicate a difference in parvalbumin positive cells in the hippocampus in MIA-treated offspring relative to controls.
Conclusions:
This study provides the first evidence that prenatal exposure to maternal immune activation alters dendritic morphology in a nonhuman primate model. Given our rapidly growing knowledge of the complex interplay between the immune and central nervous systems this may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders such as ASD.