Accumulating evidence that core phonological processing problems in language-disabled subjects may relate to more basic deficits in rapid auditory processing has introduced new possibilities for the use of animal models in the study of developmental language disorders (e.g., dyslexia). Studies performed in our lab over the past decade reveal that cortical neuronal migration anomalies (similar to those seen in post mortem brains of dyslexics) are associated with behavioral deficits in rapid auditory processing (RAP), as well as in short-term memory (STM), in rodents. Moreover, RAP deficits are larger in juvenile as compared to adult male rats, are seen following cortical neuronal migration disruption in various species, and are larger in male as compared to female rats and mice. RAP deficits are also consistently seen in the absence of overall auditory processing impairments (e.g., performance on longer-stimulus acoustic discrimination tasks is normal). Thus, convergent findings from rodent models parallels behavioral and anatomic findings from human language disabled populations in a variety of ways. These data led us to perform behavioral assessments in rats following embryonic interference with the functions of gene homologs associated (in humans) with dyslexia. We found that E14/15 transfection with RNAi for the candidate dyslexia susceptibility rat gene homolog, Dyxld, led to subsequent impairments of rapid/complex acoustic discrimination in male rats (though no deficits for discriminating longer gap stimuli were seen). Such findings have enormous translational potential for dyslexia research, by linking data across levels of genetic disruption, neurodevelopmental disruption, and disruption of cognition/ behavior. The proposed studies will continue to address the neuropathological/behavioral consequences of embryonic manipulation of rat homologs for three candidate dyslexia susceptibility genes (Dyxld, Kiaa0319, and Dcdc2). Rats undergoing embryonic transfection with RNAi (or induced gene overexpression) will be evaluated on auditory, visual, and learning/memory tasks, as well as for post mortem neuropathology. Results will be assessed for evidence of genetic and neuropathological factors associated with specific behavioral deficits in RAP and STM that parallel deficits in language-disabled humans (in contrast to more general cognitive, motor, and/or sensory deficits). Such studies may bridge the gap between disrupted brain function/behavior in dyslexics, epidemiological evidence of genetic associations with dyslexia, and the critical intervening neurodevelopmental processes that are so difficult to study in humans, but so amenable to study in rodent models.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD057853-05
Application #
8467728
Study Section
Special Emphasis Panel (ZHD1-MRG-C)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$202,419
Indirect Cost
$38,851
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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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
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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
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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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