Widespread Proliferation Impairment and Hypocellularity in the Cerebellum of Fetuses with Down Syndrome

Abstract

Evidence in mouse models for Down syndrome (DS) and human fetuses with DS clearly shows severe neurogenesis impairment in various telencephalic regions, suggesting that this defect may underlie the cognitive abnormalities of DS. As cerebellar hypotrophy and motor disturbances are part of the clinical features of DS, the goal of our study was to establish whether these defects may be related to neurogenesis impairment during cerebellar development. We found that in fetuses with DS (17-21 weeks of gestation) the cerebellum had an immature pattern, a reduced volume and notably fewer cells (-25%/-50%) in all cerebellar layers. Immunohistochemistry for Ki-67, a marker of cycling cells, showed impaired proliferation (-17%/-50%) of precursors from both cerebellar neurogenic regions (external granular layer and ventricular zone). No differences in apoptotic cell death were found in DS vs. control fetuses. The current study provides novel evidence that in the cerebellum of DS fetuses there is a generalized hypocellularity and that this defect is due to proliferation impairment, rather than to an increased cell death. The reduced proliferation potency found in the DS fetal cerebellum, in conjunction with previous evidence, strengthens the idea that the trisomic brain is characterized by widespread neurogenesis disruption.

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).…”

Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

“…Alteration of neurogenesis in neurodevelopmental disorders were studied to a lesser extent in DS (Contestabile et al, 2007;Guidi et al, 2008Guidi et al, , 2010, autism spectrum disorders (Greco et al, 2011;Wegiel et al, 2010), including Rett syndrome (Ronnett et al, 2003). Studies to understand the neurobiology of DS have benefited from the ability to examine mouse models of the disorder Kleschevnikov et al, 2004;Popov et al, 2011).…”

“…Alteration of neurogenesis under different experimental and pathological conditions has been described to a great extent (Rodriguez & Verkhratsky, 2011;Sandoval et al, 2011;Winner et al, 2011;Yoneyama et al, 2011;Yu et al, 2009). Significant decreases of neurogenesis have been found in neurodevelopmental (Contestabile et al, 2007;Guidi et al, 2008Guidi et al, , 2010 and in neurodegenerative diseases (Rodriguez & Verkhratsky, 2011). Numerous studies provide evidence that a lack of neurogenesis significantly diminishes plasticity in the adult brain and interferes with learning and memory (reviewed in Koehl & Abrous, 2011;Mongiat & Schinder, 2011).…”

Valproic Acid Decreases Cell Proliferation and Color Preference in the Zebrafish Larvae

“…Journal of Biosciences and Medicines Accumulating studies have shown that extensive reduction of neurogenesis in the developing brain may be involved in a variety of neurological functions in adult mice and humans [5] [6]. For example, severe cell proliferation defects are present in the developing neocortex, dentate gyrus, and cerebellum of mouse of Down Syndrome (DS) models [7], and the hippocampal and cerebellar regions of human fetuses with DS [8]. In the brain of zebrafish larvae cell proliferation and neurogenesis actively occur in diverse areas and are affected by external factors such as treatment with pentylenetetrazol, a GABA receptor blocker [9].…”