Prenatal treatment with the flavonoid 7,8-DHF improves trisomy-linked proliferation defects in numerous brain regions of the Ts65Dn model of Down syndrome

Intellectual disability (ID) is the unavoidable hallmark and the most invalidating feature of DS, a genetic pathology due to triplication of chromosome 21. ID in DS is mainly due to neurodevelopmental alterations among which neurogenesis reduction appears to play a prominent role. Considering the time course of brain development and that the bulk of neurogenesis takes place prenatally, therapeutic interventions aimed at correcting brain developmental defects should be started prenatally. 7,8-DHF is a natural flavonoid that crosses the blood brain barrier, and specifically binds the TrkB receptor activating its downstream signaling cascade. We previously found that neonatal treatment with 7,8-DHF improves cellularity and restores dendritic pathology in the hippocampus of the Ts65Dn mouse, the most studied DS mouse model that largely mimics the human condition. Based on these premises the goal of the current study was to establish whether prenatal treatment with 7,8-DHF is able to rescue overall brain neurogenesis. Ts65Dn pregnant females received 7,8-DHF from embryonic day 10 until delivery. In 2-days-old pups, we evaluated the number of proliferating (BrdU+) cells in various forebrain neurogenic niches. Namely, the rostral and caudal subventricular zone, dentate gyrus, rostral and caudal neocortex, striatum, thalamus and hypothalamus. We found that in treated Ts65Dn mice the proliferation potency was improved or even restored in most of the examined regions. Moreover, treatment restored cellularity in the neocortex layer II but not in the hippocampus. These results show that 7,8-DHF has a positive influence on prenatal neurogenesis and cortical cellularity in the Ts65Dn mouse model, but, unlike neonatal treatment, it has moderate effects on hippocampal cellularity. A treatment with 7,8-DHF that starts embryonically and continues in the early postnatal period should be considered as a promising strategy for the improvement of overall brain development in DS.