On dendrites in Down syndrome and DS murine models: a spiny way to learn

Abstract

Since the discovery in the 1970s that dendritic abnormalities in cortical pyramidal neurons are the most consistent pathologic correlate of mental retardation, research has focused on how dendritic alterations are related to reduced intellectual ability. Due in part to obvious ethical problems and in part to the lack of fruitful methods to study neuronal circuitry in the human cortex, there is little data about the microanatomical contribution to mental retardation. The recent identification of the genetic bases of some mental retardation associated alterations, coupled with the technology to create transgenic animal models and the introduction of powerful sophisticated tools in the field of microanatomy, has led to a growth in the studies of the alterations of pyramidal cell morphology in these disorders. Studies of individuals with Down syndrome, the most frequent genetic disorder leading to mental retardation, allow the analysis of the relationships between cognition, genotype and brain microanatomy. In Down syndrome the crucial question is to define the mechanisms by which an excess of normal gene products, in interaction with the environment, directs and constrains neural maturation, and how this abnormal development translates into cognition and behaviour. In the present article we discuss mainly Down syndrome-associated dendritic abnormalities and plasticity and the role of animal models in these studies. We believe that through the further development of such approaches, the study of the microanatomical substrates of mental retardation will contribute significantly to our understanding of the mechanisms underlying human brain disorders associated with mental retardation. #

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

“…The Ts65Dn mouse model of DS is one of the models that is most comparable to human DS both in terms of triplicated genes and phenotype (13). Similar to individuals with DS, the Ts65Dn mouse shows severe neurogenesis impairment in numerous brain regions (5, 14 -17) and less branched and less spinous dendrites (18,19) The role played by different triplicated genes in brain developmental alterations in DS is scarcely elucidated. Recent findings demonstrate that the amyloid precursor protein (APP) plays a key role in normal brain development by influencing neural precursor cell proliferation, cell fate specification, and maturation (20), which suggests that triplication of this gene may compromise these processes in the DS brain.…”

Defects in Embryonic Neurogenesis and Initial Synapse Formation in the Forebrain of the Ts65Dn Mouse Model of Down Syndrome

“…Neuropathological changes found from second trimester to birth include a smaller and hypocellular hippocampal dentate gyrus and cerebellum (Jernigan and Bellugi, 1990;Raz et al, 1995) as well as altered cortical lamination (Golden and Hyman, 1994). In addition, there are fewer synapses in the prenatal DS forebrain (Petit et al, 1984;Weitzdoerfer et al, 2001) and pyramidal neurons possess smaller dendritic arborizations in the cerebral cortex (Becker et al, 1986;Takashima et al, 1989;Benavides-Piccione et al, 2004). Postnatally, the DS brain exhibits degeneration of cortical pyramidal neurons (Schmidt-Sidor et al, 1990), profound dendrite and synapse abnormalities (Marin-Padilla, 1976;Becker et al, 1986;Takashima et al, 1989;Wisniewski, 1990), and hypocellular hippocampus and cerebral cortex (Zellweger, 1977;Sylvester, 1983).…”

Polycomb genes interact with the tumor suppressor genes hippo and warts in the maintenance of Drosophila sensory neuron dendrites

“…Whereas like-repels-like homotypic repulsion is one mechanism important for the establishment of receptive fields (Grueber et al 2003b), how tiling is maintained after the establishment of the dendritic field is not well understood. Underscoring the potential physiological significance of the maintenance of dendritic fields, dendrites of layer III cortical neurons develop normally but then degenerate postnatally in Down syndrome patients (Benavides-Piccione et al 2004). Furthermore, defects in dendrite development are the strongest correlate with mental retardation, and dendrite maintenance defects may underlie a variety of developmental disorders (Kaufmann and Moser 2000).…”