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Poster B51, Wednesday, November 8, 3:00 – 4:15 pm, Harborview and Loch Raven Ballrooms

Translational research in dyslexia: genetic rodent models inform understanding of mechanisms in humans

Tracy Centanni1,2,3, Fuyi Chen4, Anne B Booker4, Andrew M Sloan3, Sara D Beach2,5, Ola Ozernov-Palchik6, Sidney C May2, Michael P Kilgard3, Joseph J LoTurco4, Dimitrios Pantazis2, Tiffany P Hogan7, John DE Gabrieli2;1Texas Christian University, 2Massachusetts Institute of Technology, 3University of Texas at Dallas, 4University of Connecticut, 5Harvard University, 6Tufts University, 7MGH Institute of Health Professions

Introduction: Dyslexia is the most common developmental language disorder, affecting 5-15% of children and having several long-term consequences including lower self-esteem, academic and vocational difficulties, and higher delinquency rates later in life. Given the complex genetic basis of dyslexia, there is a great deal of heterogeneity within this population with respect to the underlying biological mechanisms and the corresponding behavioral deficits, although auditory perceptual and/or processing difficulties are commonly reported. Since causal genetics work is difficult in humans, research has turned to the rodent as a model system. In a rat, candidate dyslexia genes can be manipulated and the corresponding effects on sensory perception and behavioral discrimination of phonemes can be easily evaluated. However, it has been unknown whether such findings would provide applicable insights into humans with dyslexia. Methods (rat): In utero suppression of either Kiaa0319 or Dcdc2 was accomplished in Wistar rats using RNA interference. At the age of 3-6 months, neural responses to speech sounds and tones were acquired from a) experimentally naïve animals, and b) animals that underwent behavioral training on several speech sound discrimination tasks prior to neural recordings. Experimenters were blind to the genetic status of each animal during the course of all data acquisition and analysis. Methods (human): Following behavioral assessment, magnetoencephalography (MEG) data were collected from children and adults with and without dyslexia. Both children and adults were exposed to speech sounds in a passive paradigm, while adults also completed a rapid speech discrimination task. Saliva samples were acquired from children for testing of KIAA0319 markers. Results (rat): Suppression of Kiaa0319 led to increased variability in the timing of primary auditory cortex action potentials in response to speech sounds and tonal stimuli, as well as behavioral deficits on speech sound in noise and truncated speech sound discrimination tasks. Suppression of Dcdc2 did not interfere with neural consistency or with phoneme discrimination, but did cause deficits on a rapid speech sound discrimination task and interfered with neural plasticity over the course of training. Results (human): Children with dyslexia exhibited significantly higher primary auditory cortex variability compared to typically-reading peers, though not all children’s brain variance significantly differed from that of the control group. Risk markers in KIAA0319 were correlated with this finding, such that children with two risk alleles had higher variability than children with one risk allele or no risk alleles. In adults, we found neural and behavioral evidence of poorer accuracy on the rapid speech sound task in dyslexics. Conclusions: We found that genetic work in rats provided valuable insights into possible gene-brain-behavior relationships in humans with dyslexia and will play a critical role in the future to better understand gene-gene interactions in dyslexia. In humans, we identified a potential gene-brain basis for heterogeneity in dyslexia, suggesting that a better understanding of the core deficits in each individual will enable personalized assessments and interventions for those who struggle to acquire reading.

Topic Area: Language Genetics

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