Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive disability, afflicting 1 in every 800 live births. Importantly, the cause(s) of the cognitive disability in DS have not yet been uncovered. Our group has been studying the Ts65Dn mouse model of DS which has triplication of 184 of the 364 genes triplicated in DS. These mice have a large number of DS- relevant phenotypes, including cardiac and craniofacial defects as well as spatial learning/memory and motor abnormalities, the latter two of which have been principally measured in adult animals. We now report two major developmental forebrain phenotypes in Ts65Dn which precede these neurological deficits: 1) a dorsal forebrain abnormality which results in under-production of excitatory neurons and 2) a ventral forebrain defect which results in over-production of inhibitory interneurons. Together, these defects substantially shift the excitatory:inhibitory neuron ratio in Ts65Dn;we hypothesize that this is the primary cause for cognitive dysfunction in Ts65Dn/DS. Through a comprehensive set of experiments on cell proliferation, neural differentiation, gene expression and neuronal electrophysiology, we uncovered that two specific triplicated genes (the structurally linked transcription factors Olig1 and Olig2) cause the ventral Ts65Dn forebrain phenotype;we rescued the inhibitory defect in the embryonic and adult brain at the cellular and electrophysiological levels by generating Ts65DnOlig1/2? animals (reducing Olig1 and Olig2 genes from 3 to 2 alleles within the Ts65Dn background). In this period of study, we will determine whether Olig1/2 triplication influences the learning/memory and synaptic plasticity defects in Ts65Dn and investigate the role of the Dyrk1a minibrain gene in the (dorsal) excitatory neuron deficit in Ts65Dn.
Down syndrome is the most common genetic disorder resulting in mental retardation and it afflicts approximately 384,000 Americans (1:800). As such, the development of therapies for cognitive ability is critical for improving quality of life of patients and their families. In this project, we are discovering which triplicated genes lead to altered brain development and function in the Ts65Dn mouse model of Down syndrome. By reducing the dosage of three triplicated genes implicated in early brain development, this work will identify the gene targets, describe how their over-expression changes brain development and lead to prenatal and postnatal strategies for cognitive therapy.
|Onorati, Marco; Li, Zhen; Liu, Fuchen et al. (2016) Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia. Cell Rep 16:2576-92|
|Olmos-Serrano, Jose Luis; Kang, Hyo Jung; Tyler, William A et al. (2016) Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination. Neuron 89:1208-22|
|Tyler, William A; Haydar, Tarik F (2013) Multiplex genetic fate mapping reveals a novel route of neocortical neurogenesis, which is altered in the Ts65Dn mouse model of Down syndrome. J Neurosci 33:5106-19|
|Burke, Rebecca M; Norman, Timothy A; Haydar, Tarik F et al. (2013) BMP9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 110:19567-72|
|Haydar, Tarik F; Reeves, Roger H (2012) Trisomy 21 and early brain development. Trends Neurosci 35:81-91|
|Best, Tyler K; Cramer, Nathan P; Chakrabarti, Lina et al. (2012) Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome. Exp Neurol 233:749-57|
|Cramer, Nathan; Galdzicki, Zygmunt (2012) From abnormal hippocampal synaptic plasticity in down syndrome mouse models to cognitive disability in down syndrome. Neural Plast 2012:101542|
|Chakrabarti, Lina; Scafidi, Joseph; Gallo, Vittorio et al. (2011) Environmental enrichment rescues postnatal neurogenesis defect in the male and female Ts65Dn mouse model of Down syndrome. Dev Neurosci 33:428-41|
|Chakrabarti, Lina; Best, Tyler K; Cramer, Nathan P et al. (2010) Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome. Nat Neurosci 13:927-34|
|Tyler, William A; Haydar, Tarik F (2010) A new contribution to brain convolution: progenitor cell logistics during cortex development. Nat Neurosci 13:656-7|