Developing brain under renewed attack: viral infection during pregnancy.

Living in a globalized world, viral infections such as CHIKV, SARS-COV-2, and ZIKV have become inevitable to also infect the most vulnerable groups in our society. That poses a danger to these populations including pregnant women since the developing brain is sensitive to maternal stressors including viral infections. Upon maternal infection, the viruses can gain access to the fetus via the maternofetal barrier and even to the fetal brain during which factors such as viral receptor expression, time of infection, and the balance between antiviral immune responses and pro-viral mechanisms contribute to mother-to-fetus transmission and fetal infection. Both the direct pro-viral mechanisms and the resulting dysregulated immune response can cause multi-level impairment in the maternofetal and brain barriers and the developing brain itself leading to dysfunction or even loss of several cell populations. Thus, maternal viral infections can disturb brain development and even predispose to neurodevelopmental disorders. In this review, we discuss the potential contribution of maternal viral infections of three relevant relative recent players in the field: Zika, Chikungunya, and Severe Acute Respiratory Syndrome Coronavirus-2, to the impairment of brain development throughout the entire route.

Brunner syndrome associated MAOA mutations result in NMDAR hyperfunction and increased network activity in human dopaminergic neurons.

Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Among these, Monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene have been associated with Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function, specifically in dopaminergic (DA) neurons. Here we generated human induced pluripotent stem cell (hiPSC)-derived DA neurons from three individuals with Brunner syndrome carrying different mutations and characterized neuronal properties at the single cell and neuronal network level in vitro. DA neurons of Brunner syndrome patients showed reduced synaptic density but exhibited hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected in DA neurons of individuals with Brunner syndrome. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), resulting in increased NMDAR-mediated currents. By correcting a MAOA missense mutation with CRISPR/Cas9 genome editing we normalized GRIN2A and GRIN2B expression, NMDAR function and neuronal population activity to control levels. Our data suggest that MAOA mutations in Brunner syndrome increase the activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to the etiology of Brunner syndrome associated phenotypes.