Congenital Zika syndrome is associated with maternal protein malnutrition.

Zika virus (ZIKV) infection during pregnancy is associated with a spectrum of developmental impairments known as congenital Zika syndrome (CZS). The prevalence of this syndrome varies across ZIKV endemic regions, suggesting that its occurrence could depend on cofactors. Here, we evaluate the relevance of protein malnutrition for the emergence of CZS. Epidemiological data from the ZIKV outbreak in the Americas suggest a relationship between undernutrition and cases of microcephaly. To experimentally examine this relationship, we use immunocompetent pregnant mice, which were subjected to protein malnutrition and infected with a Brazilian ZIKV strain. We found that the combination of protein restriction and ZIKV infection leads to severe alterations of placental structure and embryonic body growth, with offspring displaying a reduction in neurogenesis and postnatal brain size. RNA-seq analysis reveals gene expression deregulation required for brain development in infected low-protein progeny. These results suggest that maternal protein malnutrition increases susceptibility to CZS.

Zika virus impairs the development of blood vessels in a mouse model of congenital infection.

Zika virus (ZIKV) is associated with brain development abnormalities such as primary microcephaly, a severe reduction in brain growth. Here we demonstrated in vivo the impact of congenital ZIKV infection in blood vessel development, a crucial step in organogenesis. ZIKV was injected intravenously in the pregnant type 2 interferon (IFN)-deficient mouse at embryonic day (E) 12.5. The embryos were collected at E15.5 and postnatal day (P)2. Immunohistochemistry for cortical progenitors and neuronal markers at E15.5 showed the reduction of both populations as a result of ZIKV infection. Using confocal 3D imaging, we found that ZIKV infected brain sections displayed a reduction in the vasculature density and vessel branching compared to mocks at E15.5; altogether, cortical vessels presented a comparatively immature pattern in the infected tissue. These impaired vascular patterns were also apparent in the placenta and retina. Moreover, proteomic analysis has shown that angiogenesis proteins are deregulated in the infected brains compared to controls. At P2, the cortical size and brain weight were reduced in comparison to mock-infected animals. In sum, our results indicate that ZIKV impairs angiogenesis in addition to neurogenesis during development. The vasculature defects represent a limitation for general brain growth but also could regulate neurogenesis directly.

Temporal and spatial regulation of interneuron distribution in the developing cerebral cortex--an in vitro study.

GABAergic interneurons are local circuit cells that control the excitatory balance in most regions of the nervous system, particularly the cerebral cortex. Because they are integrated in every cortical module, we posed the question whether interneuronal precursors would display some topographic specificity between their origin at the ventral telencephalon and their cortical location after migration. If this was true, GABAergic cells would have to be provided with intrinsic features that would make them able to perform specific functional roles in each specific module. On the other hand, if no topography was found, one would conclude that inhibitory precursors would be functionally naive, being able to integrate anywhere in the cortex, with equal capacity of performing their functions. This issue was approached by use of organotypic cultures of wild mice embryonic slices, into which fragments of the ganglionic eminence taken from enhanced green fluorescent protein (eGFP) mice were implanted, observing the topographic location of both the implant and its destination. Despite the existence of different genetic domains in the ventricular zone of the medial ganglionic eminences (MGE), we found that cells originating in different regions spread in vitro all over the mediolateral axis of the developing cortical wall, independently of their sites of origin. Results favor the hypothesis that GABAergic precursors are functionally naive, integrating into modules irrespective of which cortical area they belong to.