Animal models of neurodevelopmental disorders
Using animal models of neurodevelopmental diseases is a cornerstone of the way we as neuroscientists are able to pin down mechanisms by which disease pathologies arise. Thus, I was thrilled to listen to the excellent talks given at the “Animal models of neurodevelopmental disease” nanosymposium on Sunday morning. Chaired by Melissa Bauman and co-chaired by Debra Bangasser, the talks spanned across a variety of disease models. Below I highlight two talks in particular!
Zika virus: neurodegeneration in the brain and spinal cord of mouse CNS
Zika virus is a human teratogen that has resulted in one of the most critical emergency responses tackled by the CDC. Pregnant women with the infection have a high risk of fetal abnormalities called Congenital Zika Syndrome. Some of the symptoms of this condition include microcephaly, calcifications, reduced spinal cord volume, epileptic seizures, and hemorrhage of the parenchyma. But what are the neuropathological consequences of Zika infection? Kevin Noguchi and his colleagues from Washington University at St. Louis investigated this question using a mouse model.
In the study, neonatal mouse pups were inoculated with Zika virus and sacrificed two weeks later, revealing various neuropathologies similar to those seen in human offsprings. Using histological techniques, Noguchi found two main types of neurodegeneration: excitotoxicity and apoptosis. Excitotoxicity related neurodegeneration was observed in multiple brain regions including the cerebellum, cortex, hippocampus, and the striatum. Similarly, apoptotic degeneration was also observed in these regions, although to a lesser extent. In addition, apoptotic activity was seen in the funicular as well as focal degeneration in the axons within the corticospinal tract.
Fig 1. Placental pathology in Zika-infected dams is associated with severe pathology in the fetus 
It was previously known that the Zika virus affects neural progenitor cells, which are naturally eliminated over time. These outcomes indicate persistent overstimulation after Zika infection and are valuable because they suggest that the devastating consequences of the viral infection persist far along the gestational period. Such intensive effort across the global scientific community will hopefully result in rapid development, characterization, and use of animal models for the study of Zika virus biology and effects.
"Skinny" and “Branchy”: Altered dendritic morphology in the dlPFC after maternal immune activation
Scientific research within the last decade has provided evidence to suggest that maternal infection during pregnancy increases the risk for formation of psychiatric disorders in the child. For example, pregnant women with gestational exposure to influenza, other infections, and elevated levels of specific pro-inflammatory cytokines are associated with an increased risk of their child forming schizophrenia later in life. Animal models have established that the maternal immune response could be the key link between maternal infection and alterations in fetal brain development. Nevertheless, much of the mechanism by which this occurs remains unknown.
Dr. Cynthia Schumann (happy birthday!) from the UC Davis MIND Institute gave an excellent talk titled “Altered dendritic morphology in the dorsolateral prefrontal cortex of non-human primates prenatally exposed to maternal immune activation,” in the the nanosymposium on animal models of neurodevelopmental disease, elucidating some of the plausible ways by which maternal immune activation (MIA) could cause the deleterious effects on the growing fetus.
The main aim of the study was to test the hypothesis that the development of neurodevelopmental disorders such as schizophrenia is originated by dysregulation of immune molecules, which play a pivotal role in brain development. Indeed, nonhuman primates exposed to MIA display aberrant behavioral phenotypes including
- self -directed behaviors and stereotypies
- Reduced affiliative vocalizations
- Inappropriate social interactions
- Non-attendance to salient social cues
Furthermore, Schumann and her colleagues postulated that such changes can alter structural and functional connectivity, ultimately leading to disturbances in cognition, perception, and emotion.
To perform this, pregnant rhesus monkeys were randomly assigned to receive saline control injections or viral mimic polyI:C for multiple days at the end of the first trimester and blood was drawn for interleukin-6 (IL-6) analysis. The dorsolateral prefrontal cortex (dlPFC) was selected as the area of interest due to preliminary evidence of neuropathology in the region. Neurons were stained with the Golgi-Cox method to measure dendritic morphology in nonhuman primate dlPFC.
Fig 2. (left) Golgi-cox method labeled layer III pyramidal neurons, (right) overlaid 3-D reconstruction of dendritic arbors. Apical dendrite (yellow), basal dendrites (green, orange and red), axon (white) and
In the pilot cohort (n=4) Schumann and others found that 4-year old rhesus monkey offsprings exposed to MIA display altered biological development. Specifically, there was an increase in the number of oblique dendrites and decreased apical dendrite diameter in the dlPFC, aka “skinny” and “branchy” phenotype. The team found no changes in dlPFC spine density.
Apart from being a great talk, this is a promising research front that suggests that MIA could be a disease primer that impacts prenatal development and may induce susceptibility to formation of particular neurodevelopmental disease types.
 Martinot, A. J. et al. Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys. Cell 173, 1111-1122.e10 (2018).
 Weir, R. K. et al. Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. Brain Behav. Immun. 48, 139–146 (2015).