Knockdown of the Dyslexia-Associated Gene Kiaa0319 Impairs Temporal Responses to Speech Stimuli in Rat Primary Auditory Cortex

Abstract

One in 15 school age children have dyslexia, which is characterized by phoneme-processing problems and difficulty learning to read. Dyslexia is associated with mutations in the gene KIAA0319. It is not known whether reduced expression of KIAA0319 can degrade the brain's ability to process phonemes. In the current study, we used RNA interference (RNAi) to reduce expression of Kiaa0319 (the rat homolog of the human gene KIAA0319) and evaluate the effect in a rat model of phoneme discrimination. Speech discrimination thresholds in normal rats are nearly identical to human thresholds. We recorded multiunit neural responses to isolated speech sounds in primary auditory cortex (A1) of rats that received in utero RNAi of Kiaa0319. Reduced expression of Kiaa0319 increased the trial-by-trial variability of speech responses and reduced the neural discrimination ability of speech sounds. Intracellular recordings from affected neurons revealed that reduced expression of Kiaa0319 increased neural excitability and input resistance. These results provide the first evidence that decreased expression of the dyslexia-associated gene Kiaa0319 can alter cortical responses and impair phoneme processing in auditory cortex.

A high-density, high-channel count, multiplexed μECoG array for auditory-cortex recordings

“…12 and 13), as predicted from previous single and multiunit studies (Atencio and Schreiner 2012;Cheung et al 2001;Eggermont et al 2011) and subcortical stations of the auditory pathway (Rodriguez et al 2010a(Rodriguez et al , 2010b. Our study builds on these prior studies because we demonstrated that reliable, phase-locked responses to sound features can be generated from ECoG-level signals.…”

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.…”

“…As shown schematically in Figure 2B, increased glutamatergic activity disrupts the excitation-inhibition balance of cortical neurons, decreasing the precision of spike timing and increasing neural noise. Another RD risk gene homolog, Kiaa0319, has also been associated with greater trial-by-trial firing rate variability in response to speech and nonspeech sounds and with increased neural excitability in primary auditory cortex [10].…”

“…As shown schematically in Figure 2B, increased glutamatergic activity disrupts the excitation-inhibition balance of cortical neurons, decreasing the precision of spike timing and increasing neural noise. Another RD risk gene homolog, Kiaa0319, has also been associated with greater trial-by-trial firing rate variability in response to speech and nonspeech sounds and with increased neural excitability in primary auditory cortex [10].These models are complemented by human studies of neurochemistry and brain stimulation. Excitatory left hemisphere transcranial direct current stimulation (tDCS) has been shown to impair rapid auditory processing [58], consistent with a link between hyperexcitability and impairments in the prerequisite analysis of rapidly changing auditory stimuli needed for phonological processing [59].…”

“…Even among sources of hyperexcitability that may have some specificity to RD, different origins for hyperexcitability may produce subtle phenotypic differences. For example, both Kiaa0319 and Dcdc2 mutations produce phenotypes with increased neural excitability, but are associated with distinct auditory-processing deficits [3,10].Although RD is not characterized by clinically significant general cognitive impairments, the deficits associated with RD are not limited to reading and related processes. A recent study [106] showed that adults with RD do not exhibit a reduced neural response to repeated stimulus presentation (i.e., neural adaptation) to the same extent as typical readers.…”