Speech Sound Processing Deficits and Training-Induced Neural Plasticity in Rats with Dyslexia Gene Knockdown

Abstract

In utero RNAi of the dyslexia-associated gene Kiaa0319 in rats (KIA-) degrades cortical responses to speech sounds and increases trial-by-trial variability in onset latency. We tested the hypothesis that KIA- rats would be impaired at speech sound discrimination. KIA- rats needed twice as much training in quiet conditions to perform at control levels and remained impaired at several speech tasks. Focused training using truncated speech sounds was able to normalize speech discrimination in quiet and background noise conditions. Training also normalized trial-by-trial neural variability and temporal phase locking. Cortical activity from speech trained KIA- rats was sufficient to accurately discriminate between similar consonant sounds. These results provide the first direct evidence that assumed reduced expression of the dyslexia-associated gene KIAA0319 can cause phoneme processing impairments similar to those seen in dyslexia and that intensive behavioral therapy can eliminate these impairments.

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice

“…These animals do not show the expected migration deficits, and lack lamination defects or clear anomalies in the cortex; however, changes in learning, memory or auditory processing have been reported in both cases (Gabel et al 2011; Truong et al 2014; Rendall et al 2015). Similarly, in utero knockdown of Kiaa0319 in the embryonic rat cortex leads to spatial learning deficits and affect responses to complex acoustic stimuli (Szalkowski et al 2012; Centanni et al 2014a, b). We, therefore, decided to perform a general behavioural characterisation of the Kiaa0319 mutant animals to elucidate functional effects of Kiaa0319 knockout and conducted a standard series of mouse behavioural tests on a cohort of control and mutant mice.…”

“…Studies conducted with rats following in utero electroporation to knockdown Kiaa0319 (Szalkowski et al 2012; Centanni et al 2014a, b) have reported spatial learning deficits and impaired auditory processing but normal working memory using behavioural and electrophysiological tests. In the particular case of spatial learning, when assessed using the Morris water maze, these deficits were found only in animals showing also hippocampal anatomical malformations (Szalkowski et al 2012), suggesting a direct relationship between anatomical and behavioural changes.…”

“…For Kiaa0319 , these treatments led to migration defects (Paracchini et al 2006; Peschansky et al 2010; Adler et al 2013) with many targeted neurons failing to migrate and giving rise to white matter heterotopias in postnatal animals, as well as hippocampal dysplasia in some cases. In addition, behavioural studies performed with these shRNA-treated rats have also found deficits in spatial learning and rapid auditory processing, particularly with speech-like sounds (Szalkowski et al 2012; Centanni et al 2014a, b). Similar results regarding migration impairment, obtained following the same experimental approach with other candidate genes such as DCDC2 and DYX1C1, led to the hypothesis that deficits in neuronal migration during development predispose to RD (reviewed in (Gabel et al 2010)).…”

Lessons to be learned: how a comprehensive neurobiological framework of atypical reading development can inform educational practice

“…It has been shown that experimental interference of the dyslexia susceptibility genes in rodents causes atypical neuronal migration, which in turn results in localized matter malformations that affect cortical circuitry [16,17]. For example, in utero disruption of KIAA0319 expression in rats has been shown to result in poor neural representation of speech sounds in the auditory cortex and in impaired performance on phoneme discrimination tasks [18 • ,19,20]. The reported behavioral impairments in these animal studies are similar to those observed in individuals diagnosed with dyslexia [e.g., 21], especially those who showed KIAA0319 and DCDC2 variants [22].…”

Neural stability: A reflection of automaticity in reading

“…The FFR is thought to predominantly reflect activity in the auditory midbrain that faithfully captures the encoding of acoustic characteristics of speech sounds (Chandrasekaran & Kraus, 2010; White-Schwoch, Nicol, Warrier, Abrams, & Kraus, 2016) with recent evidence also suggesting a contribution from auditory cortex (Coffey, Herholz, Chepesiuk, Baillet, & Zatorre, 2016). Apart from capturing the acoustic characteristics of speech sounds, the FFR can also be examined in terms of its neural stability, capturing how consistently an individual’s brain responds to speech sounds (Centanni, Engineer, & Kilgard, 2013; Centanni et al, 2014; Hornickel & Kraus, 2013). Neural stability has often been associated with children’s reading ability (Hornickel & Kraus, 2013; White-Schwoch et al, 2015), with poor readers showing more variable FFR.…”