Commentary: Localized vs. Systematic Neurodegeneration: A Paradigm Shift in Understanding Neurodegenerative Diseases

An outbreak of births of microcephalic patients in Brazil motivated multiple studies on this incident. The data left no doubt that infection by Zika virus (ZIKV) was the cause, and that this virus promotes reduction in neuron numbers and neuronal death. Analysis of patients' characteristics revealed additional aspects of the pathology alongside the decrease in neuronal number. Here, we review the data from human, molecular, cell and animal model studies attempting to build the natural history of ZIKV in the embryonic central nervous system (CNS). We discuss how identifying the timing of infection and the pathways through which ZIKV may infect and spread through the CNS can help explain the diversity of phenotypes found in congenital ZIKV syndrome (CZVS). We suggest that intraneuronal viral transport is the primary mechanism of ZIKV spread in the embryonic brain and is responsible for most cases of CZVS. According to this hypothesis, the viral transport through the blood–brain barrier and cerebrospinal fluid is responsible for more severe pathologies in which ZIKV-induced malformations occur along the entire anteroposterior CNS axis.

Microelectrode implants are an important tool in neuroscience research and in developing brain–machine interfaces. Data from rodents have consistently shown that astrocytes are recruited to the area surrounding implants, forming a glial scar that increases electrode impedance and reduces chronic utility. However, studies in non-human primates are scarce, with none to date in marmosets. We used glial fibrillary acidic protein (GFAP) immunostaining to characterize the acute and chronic response of the marmoset brain to microelectrodes. By using densitometry, we showed that marmoset astrocytes surround brain implants and that a glial scar is formed over time, with significant increase in the chronic condition relative to the acute condition animal.

The maturation of the glymphatic system initiates fluid dynamics in the central nervous system (CNS). Here, we demonstrate that the initiating glymphatic function results in a steep reduction in the susceptibility of the CNS to Zika virus (ZIKV) infection. In mice, ZIKV injection before glymphatic system maturation leads to widespread infection, vascular deformation, and disruption of Aqp4 ⁺ astrocytic networks. After the glymphatic system formation, the same challenge fails to cause disease or persistent infection. Pharmacological inhibition of vasopressin receptor 1a, which reduces perivascular fluid dynamics, reopens the window of susceptibility to ZIKV-related disease. These findings reveal the glymphatic system as an innate protective barrier that limits viral spread in the brain parenchyma and suggest a possible explanation for why late-gestation human fetuses and newborns are less susceptible to ZIKV. Moreover, these data indicate that children with ZIKV-caused malformations can have continuous brain inflammation due to a defective glymphatic system.