Neonatal Zika virus infection causes transient perineuronal net degradation

Abstract Perineuronal nets (PNNs) form a specialized extracellular matrix that regulates neuronal activity. Their formation early in the postnatal period is regulated by neuronal signaling and glial activation raising concerns that the long-term neurological sequelae ascribed to perinatal viral infections could be mediated by altered PNN formation. Previously, we developed neonatal zika virus (ZIKV) infection model where mice have lifelong neurological sequelae despite resolving the acute infection. Here, we demonstrate that neonatal ZIKV infection results in a reduction of PNN formation during the acute disease with significant reduction in Wisteria floribunda agglutinin (WFA) staining and increased aggrecan and brevican degradants. Following resolution of infection, the level of WFA staining as well as levels of aggrecan and brevican in brains normalize, but there is increased frequency of abnormal or immature PNN. In adults, the impact of the perinatal infection subsides and PNN levels and morphology are not different from control mice. Of note, the reduction in PNN formation during acute infection was associated with increased expression of MMP12 and MMP19, but not MMP9, ADAMTS-4 or ADAMTS-5. Together our findings indicate that infection at the time of PNN development interferes with PNN formation, but nets can reform once the infection and inflammation subside.