Deleterious role of macroglial cells in two models of neurodevelopmental diseases

Astrocytes coordinate neuronal survival, synapse formation, pruning and function, participate in oligodendrocyte differentiation and integrate the neurovascular unit (NVU). Thus, early defects in astrocytes may contribute to the onset and progression of neurodevelopmental disorders. Here, we investigated the role of astrocytes on myelination and NVU function in glutaric acidemia type-I (GA-I) and maternal iron deficiency (ID). GA-I is an inherited neurometabolic disease characterized by striatal neurodegeneration, dismyelination, and vascular dysfunction upon cerebral accumulation of glutaric (GA) and 3-hydroxyglutaric acids, but through not fully understood mechanisms. The GA intracisternal injection to newborn rats, elicited increased proliferation of immature neurotoxic astrocytes at 1-5 days post-injection. At 12-30 days later, the striatum showed exacerbated ER stress and nuclear envelope swelling in oligodendrocytes; dismyelination and Evans Blue extravasation to the striatal parenchyma together with decreased aquaporin 4 (AQP4) and pericyte areas associated with small blood vessels. GA did not show direct effects on oligodendrocytes or pericytes but the conditioned media from GA-treated astrocytes had increased expression of pro-inflammatory cytokines and growth factors that might affect all neural cells. Concerning ID, this prevalent health problem irreversibly damages brain development and myelination, but NVU is poorly studied. Blood samples of rat pups from mothers fed with ID diet since embryonic day 5 till weaning, showed severe microcytic hypochromic anemia at 14 but not at 30 postnatal-day. However, at this age, the corpus callosum showed severe hypomyelination and immature astrocytes. In CA1 hippocampal region, ID AQP4+ capillaries were shorter than controls, had less AQP4 and fewer associated pericytes. Blood brain barrier disruption was not seen at the ages analyzed. Therefore, in the GA-I and ID models analyzed, macroglial cells and pericytes were directly or indirectly affected and could have deleterious effects on proper myelination or NVU function, thus contributing to systemic CNS damage. None.