Reversing neural circuit and behavior deficit in mice exposed to maternal inflammation by Zika virus

Zika virus (ZIKV) infection during pregnancy is linked to various developmental brain disorders. Infants who are asymptomatic at birth might have postnatal neurocognitive complications. However, animal models recapitulating these neurocognitive phenotypes are lacking, and the circuit mechanism underlying behavioral abnormalities is unknown. Here, we show that ZIKV infection during mouse pregnancy induces maternal immune activation (MIA) and leads to autistic-like behaviors including repetitive self-grooming and impaired social memory in offspring. In the medial prefrontal cortex (mPFC), ZIKV-affected offspring mice exhibit excitation and inhibition imbalance and increased cortical activity. This could be explained by dysregulation of inhibitory neurons and synapses, and elevated neural activity input from mPFC-projecting ventral hippocampus (vHIP) neurons. We find structure alterations in the synaptic connections and pattern of vHIP innervation of mPFC neurons, leading to hyperconnectivity of the vHIP-mPFC pathway. Decreasing the activity of mPFC-projecting vHIP neurons with a chemogenetic strategy rescues social memory deficits in ZIKV offspring mice. Our studies reveal a hyperconnectivity of vHIP to mPFC projection driving social memory deficits in mice exposed to maternal inflammation by ZIKV. SYNOPSIS This study presents a new mouse model of congenital Zika syndrome with neurocognitive dysfunctions. It reveals local and long-range neural circuit defects driving autistic-like behaviors in offspring mice exposed to maternal inflammation by Zika virus. 1ZIKV infection during pregnancy induces maternal and fetal brain inflammation and leads to autistic-like behaviors in offspring mice. ZIKV-affected offspring mice show cortical hyperexcitability due to E:I imbalance. A hyperconnectivity of ventral hippocampus (vHIP) to medial prefrontal cortex (mPFC) neural circuit drives social memory deficit in ZIKV offspring mice. Graphical Abstract This study presents a new mouse model of congenital Zika syndrome with neurocognitive dysfunctions. It reveals local and long-range neural circuit defects driving autistic-like behaviors in offspring mice exposed to maternal inflammation by Zika virus.