Progress towards a cellular neurobiology of reading disability

Abstract

Reading Disability (RD) is a significant impairment in reading accuracy, speed and/or comprehension despite adequate intelligence and educational opportunity. RD affects 5-12% of readers, has a well-established genetic risk, and is of unknown neurobiological cause or causes. In this review we discuss recent findings that revealed neuroanatomic anomalies in RD, studies that identified 3 candidate genes (KIAA0319, DYX1C1, and DCDC2), and compelling evidence that potentially link the function of candidate genes to the neuroanatomic anomalies. A hypothesis has emerged in which impaired neuronal migration is a cellular neurobiological antecedent to RD. We critically evaluate the evidence for this hypothesis, highlight missing evidence, and outline future research efforts that will be required to develop a more complete cellular neurobiology of RD.

Figure 1

Summary of RNAi studies demonstrating a role for Kiaa0319, Dcdc2, and Dyx1c1 in neuronal migration in the developing neocortex. A) Example images of eGFP (green) labeled neurons in a patch of embryonic neocortex 4 days after four different manipulations. “Control” shows the normal dispersion pattern of neurons after they have migrated.” Kiaa0319”, “Dcdc2”, and “Dyx1c1” panels show the effects on cell dispersion and migration following RNAi knockdown of the indicated candidate gene. Note that in each condition the vast majority of cells fail to disperse by migration, and that each RNAi condition creates a somewhat distinct pattern. B) A summary of RNAi results for both short-term and long-term effects of RNAi targeted against candidate genes (Burbridge TJ et al., 2008; Meng H, SD Smith et al., 2005; Paracchini S et al., 2006; Rosen GD et al., 2007; Wang Y et al., 2006). After 4 days of migration cells targeted with RNAi are largely stalled, but when examined in the adult brain the RNAi treatments caused a final phenotype that included normally positioned neurons, a mixture of heterotopia and ectopia, as well as scattered neuronal displacement. C) Example of three types of malformations resulting from Dyx1c1 RNAi and examined in the mature rat brain: ectopia (small arrows), white matter heterotopia (open arrows) and hipocampal dysplasia (arrow points). In the lower panel transfected cells are labeled brown (Rosen GD et al., 2007).