Cell cycle alteration and decreased cell proliferation in the hippocampal dentate gyrus and in the neocortical germinal matrix of fetuses with down syndrome and in Ts65Dn mice

The fetal cortex, cerebellum and hippocampus have all been shown to contain fewer neurons in individuals with Down syndrome than in controls, albeit based on small sample sizes.

“The fetal cortex, cerebellum and hippocampus have all been shown to contain fewer neurons in individuals with DS than in controls40–48, albeit based on small sample sizes17.”

The presence of fewer cycling cells and the reduced number of progenitors both support the suggestion that neurogenesis is reduced during development in Down syndrome, although these data do not distinguish between slower progenitor proliferation or premature progenitor cell cycle exit.

“Together, the presence of fewer cycling cells and the reduced number of progenitors both support the suggestion that neurogenesis is reduced during development in DS, although these data do not distinguish between slower progenitor proliferation or premature progenitor cell cycle exit.”

Analyses of fetal brain tissue indicate that there are fewer proliferating cells, as measured by expression of the cell cycle marker Ki67 and of cyclin proteins, in the germinal zones of the hippocampus and cortex in Down syndrome.

“Analyses of fetal brain tissue indicate that there are fewer proliferating cells, as measured by their expression of the cell cycle marker Ki67 and of cyclin proteins, in the germinal zones of the hippocampus and cortex in DS40,42–44,47,50,64.”

Reductions in the number of proliferating neural progenitor cells in the dentate gyrus, germinal matrix of the lateral ventricle, and third ventricle have been observed in tissue derived from fetuses diagnosed with Down syndrome (17-21 weeks gestation) prior to the initial observations of volumetric changes.

“Reductions in the number of proliferating neural progenitor cells (NPCs) in the dentate gyrus, germinal matrix of the lateral ventricle, and third ventricle have all been observed in tissue derived from fetuses diagnosed with DS (17–21 weeks gestation) prior to the initial observations of volumetric changes (Contestabile et al., 2007; Stagni et al., 2020).”

Ts65Dn show an increased percentage of cells with astroglial morphology in the hippocampus.

“This astroglia shift has also been observed in Ts65Dn with an increased percentage of cells showing astroglial morphology in the hippocampus (Contestabile et al., 2007).”

In Ts65Dn, the number of actively proliferating cells in the germinal zone of the dorsal telencephalon is decreased and this deficit persists postnatally, with fewer proliferating cells being found in the hippocampus.

“In concert, the number of actively proliferating cells in the germinal zone of the dorsal telencephalon is decreased (Aziz et al., 2018; Shaw et al., 2020) and this deficit persists postnatally, with fewer proliferating cells being found in the hippocampus (Contestabile et al., 2007).”

Human studies show decreased cerebral volume due in part to hypocellularity driven by decreased NPC proliferation.

“One of the best documented phenotypes observed from human studies is the decreased cerebral volume thought to be due in part to hypocellularity driven by a decrease in NPC proliferation (Contestabile et al., 2007; Stagni et al., 2020).”