Stuttering-induced epigenetic modifications of the Ca 2+ - dependent K + and hyperpolarization-activated inward currents in the basal-ganglia projecting cortical neurons of songbirds

Abstract

Stuttering is a neurodevelopmental disorder marked by disrupted speech flow characterized by repetition of sounds, syllables, or words; prolongation of sounds; and interruptions in speech known as blocks. Despite its importance and our current advances in technology, the pathophysiological mechanisms of stuttering remain largely unknown. Vocal control and learning in both songbirds and humans rely heavily on auditory feedback. Continuous delayed auditory feedback (cDAF) is a technique that has been shown to significantly disrupt speech fluency in humans and induce stuttering in songbirds. Focusing on the cortical nucleus HVC, a crucial area in the song system necessary for song learning and production, we examined the intrinsic neuronal properties of a major class of neurons known as the basal-ganglia projecting HVC neurons, which had been shown to exhibit altered firing behaviors under stuttering conditions. Building on a biophysically realistic mathematical model incorporating ionic currents which had been pharmacologically identified for this class, we started by constructing an error function customized to this class of neurons given their characteristic spiking patterns, with the aim of generating excellent fits and predictions between the biological recordings and model simulations. We then used bifurcation analysis to study the behavior of the dynamical system and conducted exhaustive parameter searches on a high-performance computing cluster at the American University of Beirut, where we explored a relatively large space of key parameters that had been identified by the bifurcation analysis and that govern the neuronal behavior. The intensive parameter searches were conducted on two datasets of basal-ganglia projecting neurons, a control group of adult zebra finches (N=160 neurons from 35 birds) and another adult group (N=60 neurons from 9 birds) that had been subjected to cDAF for ≥6 days leading to their stuttering. Our model simulations highlighted key roles for two principle ionic channels that had been modified during stuttering leading to the changes observed in the corresponding firing behaviors. In particular, stuttering induced a down-regulation in the Ca2+- dependent K+ current (I_SK) and an upregulation in the hyperpolarization-activated inward current (I_H). Our results link, for the first time, possible channelopathies or epigenetic modifications in I_SK and I_H to the stuttering neurological disorder after cDAF induction. Further basic and clinical follow up have the potential to develop new therapeutics for managing stuttering.