Neocortical disruption and behavioral impairments in rats following in utero RNAi of candidate dyslexia risk gene Kiaa0319.
Within the last decade several genes have been identified as candidate risk genes for developmental dyslexia. Recent research using animal models and embryonic RNA interference (RNAi) has shown that a subset of the candidate dyslexia risk genes--DYX1C1, ROBO1, DCDC2, KIAA0319--regulate critical parameters of neocortical development, such as neuronal migration. For example, embryonic disruption of the rodent homolog of DYX1C1 disrupts neuronal migration and produces deficits in rapid auditory processing (RAP) and working memory--phenotypes that have been reported to be associated with developmental dyslexia. In the current study we used a modified prepulse inhibition paradigm to assess acoustic discrimination abilities of male Wistar rats following in utero RNA interference targeting Kiaa0319. We also assessed spatial learning and working memory using a Morris water maze (MWM) and a radial arm water maze. We found that embryonic interference with this gene resulted in disrupted migration of neocortical neurons leading to formation of heterotopia in white matter, and to formation of hippocampal dysplasia in a subset of animals. These animals displayed deficits in processing complex acoustic stimuli, and those with hippocampal malformations exhibited impaired spatial learning abilities. No significant impairment in working memory was detected in the Kiaa0319 RNAi treated animals. Taken together, these results suggest that Kiaa0319 plays a role in neuronal migration during embryonic development, and that early interference with this gene results in an array of behavioral deficits including impairments in rapid auditory processing and simple spatial learning.
Department of Psychology/Behavioral Neuroscience, University of Connecticut, 406 Babbidge Road, Unit 1020, Storrs, CT 06269, USA. Caitlin.cleary@uconn.edu
Caitlin E
CE
Szalkowski
Christopher G
CG
Fiondella
Albert M
AM
Galaburda
Glenn D
GD
Rosen
Joseph J
JJ
Loturco
R Holly
RH
Fitch
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D004410:Dyslexia / Q000150:complications / Q000235:genetics / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000502:physiology; D001523:Mental Disorders / Q000209:etiology* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D019579:Neocortex / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D034622:RNA Interference / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic
D003598:Cytoskeletal Proteins; C478878:DNAAF4 protein, human; C500377:KIAA0319 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins