Recent evidence indicates that candidate dyslexia susceptibility genes (CDSGs) have roles in the development of the cerebral cortex, especially in neuronal migration and maturation. In Project II, we will investigate postnatal anatomic consequences of neuronal migration disorders induced by embryonic transfection with small hairpin RNAs (shRNA) targeted against CDSG homologs Dyxld, Kiaa0319, or Dcdc2 in the rat cerebral cortex. Based on preliminary results, and because it is not yet known in humans whether all of these gene variants result in loss of function, we will also investigate the effects of CDSG overexpression. Since all CDSGs share among them an association with dyslexia, in Aim 1 we will address anatomical RNAi and overexpression phenotypes that appear to be shared among the genes?namely a bimodal distribution of transfected cells that either undermigrate or migrate past their expected laminar locations. We will use molecular and birthdate markers to assess the phenotypes of these mismigrated neurons, whether or not layer appropriate. In addition, we will co-transfect gain and loss of function neurons with a wheat germ agglutinin transgene that will allow precise determination of the connectivity of transfected neurons in both control and experimental cases. We will compare the intra- and inter-hemispheric, cortico-cortical, cortico-thalamic, and thalamo-cortical connections in rats transfected with different CDSG shRNAs, as well as between experimentals and controls. In the expectation that this work can guide research on dyslexia subtyping, Aim 2 will focus on systematic differences that are seen in the brains of rats embryonically transfected with shRNA or overexpression plasmids for each of the CDSG homologs. Following completed work in embryos, we will use in situ hybridization and immunohistochemistry to compare the genes'temporal and spatial expression patterns in the postnatal rat. We will also assess the neuronal morphology of transfected neurons and their processes.
Aim 3 examines widespread changes in anatomic organization, which are hypothesized to arise directly from local transfections of shRNA or overexpression constructs and as a result of secondary plasticity-related effects. We will use efficient and accurate stereologic probes to estimate neuron number, neuron size, and regional volume throughout the neocortex and thalamus. An accurate description of the forebrain anatomy that results from either knockdown or overexpression of rat homologs of CDSGs, both cell autonomous and secondary effects, and the course of their development, serve as a good bridge between genetics and behavior and will help to shed a broader light on the neurobiological substrates underlying developmental dyslexia in humans. We will link results from this project down to developmental and molecular mechanisms studied in Project I and up to behavioral changes to be characterized in Project III.
|Rendall, Amanda R; Ford, Aiden L; Perrino, Peter A et al. (2017) Auditory processing enhancements in the TS2-neo mouse model of Timothy Syndrome, a rare genetic disorder associated with autism spectrum disorders. Adv Neurodev Disord 1:176-189|
|Rendall, Amanda R; Tarkar, Aarti; Contreras-Mora, Hector M et al. (2017) Deficits in learning and memory in mice with a mutation of the candidate dyslexia susceptibility gene Dyx1c1. Brain Lang 172:30-38|
|Che, Alicia; Truong, Dongnhu T; Fitch, R Holly et al. (2016) Mutation of the Dyslexia-Associated Gene Dcdc2 Enhances Glutamatergic Synaptic Transmission Between Layer 4 Neurons in Mouse Neocortex. Cereb Cortex 26:3705-3718|
|Chen, Fuyi; Becker, Albert; LoTurco, Joseph (2016) Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery. Curr Protoc Pharmacol 72:14.37.1-12|
|Rendall, Amanda R; Truong, Dongnhu T; Fitch, R Holly (2016) Learning delays in a mouse model of Autism Spectrum Disorder. Behav Brain Res 303:201-7|
|Truong, Dongnhu T; Rendall, Amanda R; Rosen, Glenn D et al. (2015) Morphometric changes in subcortical structures of the central auditory pathway in mice with bilateral nodular heterotopia. Behav Brain Res 282:61-9|
|Truong, D T; Che, A; Rendall, A R et al. (2014) Mutation of Dcdc2 in mice leads to impairments in auditory processing and memory ability. Genes Brain Behav 13:802-11|
|Che, Alicia; Girgenti, Matthew J; LoTurco, Joseph (2014) The dyslexia-associated gene DCDC2 is required for spike-timing precision in mouse neocortex. Biol Psychiatry 76:387-96|
|Centanni, T M; Booker, A B; Sloan, A M et al. (2014) Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex. Cereb Cortex 24:1753-66|
|Siddiqi, Faez; Chen, Fuyi; Aron, Abraham W et al. (2014) Fate mapping by piggyBac transposase reveals that neocortical GLAST+ progenitors generate more astrocytes than Nestin+ progenitors in rat neocortex. Cereb Cortex 24:508-20|
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