Forebrain Neural Precursor Cells Are Differentially Vulnerable to Zika Virus Infection.

Prenatal exposure to Zika virus (ZIKV) can result in microencephaly and congenital Zika syndrome, although some brain cells and structures are spared by the virus for unknown reasons. Here, a novel murine model of fetal ZIKV infection incorporating intraventricular infection and cell type-specific in utero electroporation (IUE) was used to identify the time course of ZIKV infection and to determine the identity of cells that are initially infected or spared during neocortical neurogenesis. In vivo time course studies revealed the presence of ZIKV in apical radial glial cells (aRGCs) at early time points following virus exposure, while basal intermediate progenitor cells (bIPCs) became maximally (ZIKV+) after 3 d of virus exposure. ZIKV-infected fetal brains exhibited microencephaly as early as 1 d following infection, regardless of developmental age. This change in brain size was caused in part by apoptosis and reduced proliferation that persisted until birth. While 60% of aRGC basal fibers were perturbed during infection, 40% retained normal morphology, indicating that aRGCs are not uniformly vulnerable to ZIKV infection. To investigate this heterogeneous vulnerability, we performed genetic fate mapping using cell type-specific probes derived from a mouse embryonic day (E)15.5 neocortical wall single-cell RNA sequencing (scRNAseq) dataset. The results indicate that one class of aRGCs preferentially express the putative ZIKV entry receptor AXL and that these cells are more vulnerable to ZIKV infection than other aRGC subtypes with low AXL expression. Together, these data uncover crucial temporal and cellular details of ZIKV fetal brain infection for prevention strategies and for management of congenital Zika syndrome.

Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons.

Human mutations in CNTNAP2 are associated with an array of neuropsychiatric and neurological syndromes, including speech and language disorders, epilepsy, and autism spectrum disorder (ASD). We examined Cntnap2's expression and function in GABAergic cortical interneurons (CINs), where its RNA is present at highest levels in chandelier neurons, PV+ neurons and VIP+ neurons. In vivo functions were studied using both constitutive Cntnap2 null mice and a transplantation assay, the latter to assess cell autonomous phenotypes of medial ganglionic eminence (MGE)-derived CINs. We found that Cntnap2 constitutive null mutants had normal numbers of MGE-derived CINs, but had reduced PV+ CINs. Transplantation assays showed that Cntnap2 cell autonomously regulated the physiology of parvalbumin (PV)+, fast-spiking CINs; no phenotypes were observed in somatostatin+, regular spiking, CINs. We also tested the effects of 4 human CNTNAP2 ASD missense mutations in vivo, and found that they impaired PV+ CIN development. Together, these data reveal that reduced CNTNAP2 function impairs PV+ CINs, a cell type with important roles in regulating cortical circuits.