The proposed Program Project is to study a unique rat model of developmental learning disability that uses methods of developmental neurobiology, structural anatomy, and behavior to analyze the functions of three candidate dyslexia susceptibility genes (CDSGs). Neuropathologic studies in human dyslexic brains and previous animal models have underscored the importance of focal neuronal migration defects and developmental plasticity for some of the dyslexic deficits. The discovery of CDSGs challenges us to analyze the effects of this genetic variation on brain development, structure, and behavior with respect to learning disability. Using an in utero electroporation method developed in our laboratories, we will transfect into young neurons in the ventricular zone short hairpin RNAs or over-expression constructs targeted against homologs in the rat of CDSG Dyxicl, Kiaa0319, or Dcdc2. We have already seen that this procedure leads to abnormal neuronal migration, alters neuronal morphology, and causes secondary effects in untouched neighboring neurons, thus producing a picture reminiscent of dyslexic brains. Interesting behavioral alterations are also seen. Project I (J.J. LoTurco, PI) will analyze Dyxicl's interaction with genes with known molecular pathways involved in process extension, nuclear movement, and cell adhesion, the domains on the Dyxicl critical to function. Project II (A.M. Galaburda, PI) will characterize anatomic changes (cortical architecture, cell identity, morphology, and connectivity) associated with knockdown or overexpression of CDSGs. Project III (H. Fitch, PI) will uncover behavioral consequences of CDSG disruption (auditory processing and learning), and will attempt to ameliorate the effects of these genetic manipulations by behavioral interventions. The three interactive projects will be supported by an Administrative Core, an In Utero Electroporation Core, and a Neurohistology, Morphometry, and Data Processing Core. A better understanding of the functions of CDSGs will shed a broader light on mechanisms of normal brain development and on the abnormalities seen in developmental dyslexia, but also offering the possibility of earlier detection, biologically-based subtyping, and improved treatment.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057853-04
Application #
8300220
Study Section
Special Emphasis Panel (ZHD1-MRG-C (GA))
Program Officer
Miller, Brett
Project Start
2009-09-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$993,302
Indirect Cost
$243,496
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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
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
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
Truong, Dongnhu T; Bonet, Ashley; Rendall, Amanda R et al. (2013) A behavioral evaluation of sex differences in a mouse model of severe neuronal migration disorder. PLoS One 8:e73144
Platt, M P; Adler, W T; Mehlhorn, A J et al. (2013) Embryonic disruption of the candidate dyslexia susceptibility gene homolog Kiaa0319-like results in neuronal migration disorders. Neuroscience 248C:585-593
Szalkowski, Caitlin E; Fiondella, Christopher F; Truong, Dongnhu T et al. (2013) The effects of Kiaa0319 knockdown on cortical and subcortical anatomy in male rats. Int J Dev Neurosci 31:116-22
Szalkowski, Caitlin E; Booker, Anne B; Truong, Dongnhu T et al. (2013) Knockdown of the candidate dyslexia susceptibility gene homolog dyx1c1 in rodents: effects on auditory processing, visual attention, and cortical and thalamic anatomy. Dev Neurosci 35:50-68
Tarkar, Aarti; Loges, Niki T; Slagle, Christopher E et al. (2013) DYX1C1 is required for axonemal dynein assembly and ciliary motility. Nat Genet 45:995-1003
LoTurco, Joseph J; Tarkar, Aarti (2013) DYX1C1 placed in a molecular context. Biol Psychiatry 73:497-8
Adler, William T; Platt, Maryann P; Mehlhorn, Alison J et al. (2013) Position of neocortical neurons transfected at different gestational ages with shRNA targeted against candidate dyslexia susceptibility genes. PLoS One 8:e65179

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