RESEARCH ARTICLE: Neurogenesis Impairment and Increased Cell Death Reduce Total Neuron Number in the Hippocampal Region of Fetuses with Down Syndrome

Abstract

We previously obtained evidence for reduced cell proliferation in the dentate gyrus (DG) of fetuses with Down syndrome (DS), suggesting that the hippocampal hypoplasia seen in adulthood may be caused by defective early neuron production. The goal of this study was to establish whether DS fetuses (17-21 weeks of gestation) exhibit reduction in total cell number in the DG, hippocampus and parahippocampal gyrus (PHG). Volumes of the cellular layers and cell number were estimated with Cavalieri's principle and the optical fractionator method, respectively. We found that in DS fetuses all investigated structures had a reduced volume and cell number. Analysis of cell phenotype showed that DS fetuses had a higher percentage of cells with astrocytic phenotype but a smaller percentage of cells with neuronal phenotype. Immunohistochemistry for Ki-67, a marker of cycling cells, showed that DS fetuses had less proliferating cells in the germinal zones of the hippocampus and PHG. We additionally found that in the hippocampal region of DS fetuses there was a higher incidence of apoptotic cell death. Results show reduced neuron number in the DS hippocampal region and suggest that this defect is caused by disruption of neurogenesis and apoptosis, two fundamental processes underlying brain building.

The Amyloid Precursor Protein (APP) Triplicated Gene Impairs Neuronal Precursor Differentiation and Neurite Development through Two Different Domains in the Ts65Dn Mouse Model for Down Syndrome

“…Consistently with this idea, recent evidence has shown a severe impairment of cellular proliferation in the ventricular germinal matrix and various structures of the hippocampal region and cerebellum of human fetuses with DS (5)(6)(7). This proliferation impairment is worsened by impaired cell fate specification with a reduction in neuronogenesis and an increase in astrogliogenesis (5)(6)(7). This evidence suggests that proliferation impairment and cell fate specification may be key determinants of intellectual disability in individuals with DS.…”

“…The hypocellularity observed in the primary visual cortex, primary somatosensory cortex, primary motor cortex, primary auditory cortex, and superior temporal gyrus of individuals with DS led to the hypothesis that proliferation deficits may underlie the typical hypocellularity of the DS brain (3,4). Consistently with this idea, recent evidence has shown a severe impairment of cellular proliferation in the ventricular germinal matrix and various structures of the hippocampal region and cerebellum of human fetuses with DS (5)(6)(7). This proliferation impairment is worsened by impaired cell fate specification with a reduction in neuronogenesis and an increase in astrogliogenesis (5)(6)(7).…”

Nurturing brain plasticity: impact of environmental enrichment

“…[149][150][151][152][153][154] At the cellular level, Ts65Dn mice have a reduced number of hippocampal and cerebellar neurons, 155,156 impaired neurogenesis in the dentate gyrus of the hippocampus in both young and aged adults 157,158 and a prominent reduction in dendritic branching in several brain regions, accompanied by alterations in spine size and shape. 159 It is noteworthy that DS is also associated with reduced hippocampal neurogenesis 160 and volume 161 in humans. Adult Ts65Dn mice show age-dependent degeneration of basal forebrain cholinergic neurons (BFCNs), 162 the most characteristic neuropathological correlate of the late cognitive decline observed in Alzheimer's disease (AD).…”

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

“…The DS brain is characteristically small, and accumulating evidence in human fetuses with DS and DS mouse models clearly shows that this defect is due to widespread neurogenesis impairment that can be traced back to very early developmental stages. [2][3][4][5][6][7] Consequently, neurogenesis defects leading to brain hypocellularity appear to be a major determinant of cognitive disability in DS.…”