Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1.
Developmental malformations of cortex have been shown to co-occur with language, learning, and other cognitive deficits in humans. Rodent models have repeatedly shown that animals with such developmental malformations have deficits related to auditory processing and learning. More specifically, freeze-lesion induced microgyria as well as molecular layer ectopias have been found to impair rapid auditory processing ability in rats and mice. In humans, deficits in rapid auditory processing appear to relate to later impairments of language. Recently, genetic variants of four different genes involved in early brain development have been proposed to associate with an elevated incidence of developmental dyslexia in humans. Three of these, DYX1C1, DCDC2, and KIAA0319, have been shown by in utero RNAi to play a role in neuronal migration in developing neocortex. The present study assessed the effects of in utero RNAi of Dyx1c1 on auditory processing and spatial learning in rats. Results indicate that RNAi of Dyx1c1 is associated with cortical heterotopia and is suggestive of an overall processing deficit of complex auditory stimuli in both juvenile and adult periods (p=.051, one-tail). In contrast, adult data alone reveal a significant processing impairment among RNAi treated subjects compared to shams, indicating an inability for RNAi treated subjects to improve detection of complex auditory stimuli over time (p=.022, one-tail). Further, a subset of RNAi treated rats exhibited hippocampal heterotopia centered in CA1 (in addition to cortical malformations). Malformations of hippocampus were associated with robust spatial learning impairment in this sub-group (p<.01, two-tail). In conclusion, in utero RNAi of Dyx1c1 results in heterogeneous malformations that correspond to distinct behavioral impairments in auditory processing, and spatial learning.
Threlkeld
Steven W
SW
Department of Psychology, Behavioral Neuroscience Division, University of Connecticut, 806 Babbidge Road, Storrs, CT 06269-1020, USA.
McClure
Melissa M
MM
Bai
Jilin
J
Wang
Yu
Y
LoTurco
Joe J
JJ
Rosen
Glenn D
GD
Fitch
R Holly
RH
D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001308:Auditory Perceptual Disorders / Q000209:etiology*; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D004410:Dyslexia / Q000150:complications* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D007859:Learning Disabilities / Q000209:etiology*; D018782:Maze Learning / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013028:Space Perception / Q000502:physiology; D014162:Transfection / Q000379:methods; D014599:Uterus / Q000502:physiology
D003598:Cytoskeletal Proteins; C478878:DNAAF4 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins