Mutation of the dyslexia-associated geneDcdc2impairs LTM and visuo-spatial performance in mice

Abstract

Developmental reading disorder (RD) affects 5–10% of school aged children (American Psychiatric Association, 2000), with a heritability of approximately 60% (Astrom et al., 2011). Genetic association studies have identified several candidate RD susceptibility genes, including DCDC2, however a direct connection between the function of these genes and cognitive or learning impairments remains unclear (Gabel et al., 2010, Paracchini et al., 2007). Variants in DCDC2, a member of the doublecortin family of genes, have been associated in humans with RD and ADHD and Dcdc2 may play a role in neuronal migration in rats (Burbridge et al., 2008, Meng et al., 2005). In this study, we examined the effect of dcdc2 mutation on cognitive abilities in mice using a visual attention and visuo-spatial learning and memory task. We demonstrate that both heterozygous and homozygous mutations of Dcdc2 result in persistent visuo-spatial memory deficits, as well as visual discrimination and long-term memory deficits. These behavioral deficits occur in the absence of neuronal migration disruption in the mutant mice, and may be comorbid with an anxiety phenotype. These are the first results to suggest a direct relationship between induced mutation in Dcdc2 and changes in behavioral measures. Dcdc2 mutant mice should prove useful in future studies designed to further dissect the underlying neural mechanisms that are impaired following Dcdc2 mutation.

Neural Noise Hypothesis of Developmental Dyslexia

“…An increasing number of studies have investigated the function of RD risk genes in animal models [2][3][4][5][6][7][8][9][10][11][12][13], and the neurobiological and behavioral consequences of genetic RD risk variants in humans [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], motivating the need for a synthesis of these findings, especially because they relate to emerging avenues of human research on the role of neurochemistry [32] and neural oscillations [33][34][35][36] in RD. Here, we present a timely integration of diverse lines of current research linking some of the key neural and behavioral deficits associated with RD to basic neural processes.…”

Translating dyslexia across species

“…Their results show that mutation of Dcdc2 resulted in persistent visuo-spatial memory, visual discrimination, and long-term memory deficits. These data suggest a direct relationship between induced mutation in Dcdc2 and changes in behavioral measures (Gabel et al, 2011). Determining whether there are unique behavioral phenotypes associated with DCDC2 in humans may inform early detection and intervention protocols for this specific phenotype.…”

“…The Hebb-Williams (HW) maze task, a closed-field maze consisting of 12 distinct configurations, with three measured levels of difficulty (Hebb & Williams, 1946;Rabinovitch & Rosvold, 1951;Meunier, Saint-Marc, & Destrade, 1986), has been used to examine visuo-spatial abilities in a wide range of species (e.g., rodents, rabbits, nonhuman primates). Animal models of dyslexia, which include mice with neocortical malformations similar to those identified in humans with reading disorder (Boehm et al, 1996;Hoplight, Sherman, Hyde, & Denenberg, 2001) and mice with a Dcdc2 mutation (Gabel et al 2011), exhibit impaired performance on this task. A virtual version of the Hebb-Williams maze allows for examination of spatial cognition, including visual attention, visuo-spatial processes, and spatial cuing.…”

“…For example, Gabel et al (2011) examined the effect of Dcdc2 mutation on cognitive abilities in mice using a visual attention and visuospatial learning and memory task. Their results show that mutation of Dcdc2 resulted in persistent visuo-spatial memory, visual discrimination, and long-term memory deficits.…”

Insights into the Genetic Foundations of Human Communication

“…For example, DYX1C1 has been shown to play a role in the primary cilium and mutations of this gene are now known to cause a monogenic form of the disorder primary ciliary dyskinesis (Carrion-Castillo et al 2013;Tarkar et al 2013). In utero gene knockdown in rats has been a major strategy for examining the role of dyslexia candidate genes in brain development (Szalkowski et al 2012;Threlkeld et al 2007;Gabel et al 2011). These experiments have consistently produced deficits in neuronal migration that were intriguing in the light of an early report of heterotopias in postmortem brains from individuals with dyslexia (Galaburda et al 1985).…”