Kv7 channels regulate pairwise spiking covariability in health and disease

Abstract

Ocker GK, Doiron B. Kv7 channels regulate pairwise spiking covariability in health and disease. J Neurophysiol 112: 340 -352, 2014. First published April 30, 2014 doi:10.1152/jn.00084.2014.-Low-threshold M currents are mediated by the Kv7 family of potassium channels. Kv7 channels are important regulators of spiking activity, having a direct influence on the firing rate, spike time variability, and filter properties of neurons. How Kv7 channels affect the joint spiking activity of populations of neurons is an important and open area of study. Using a combination of computational simulations and analytic calculations, we show that the activation of Kv7 conductances reduces the covariability between spike trains of pairs of neurons driven by common inputs. This reduction is beyond that explained by the lowering of firing rates and involves an active cancellation of common fluctuations in the membrane potentials of the cell pair. Our theory shows that the excess covariance reduction is due to a Kv7-induced shift from low-pass to band-pass filtering of the single neuron spike train response. Dysfunction of Kv7 conductances is related to a number of neurological diseases characterized by both elevated firing rates and increased network-wide correlations. We show how changes in the activation or strength of Kv7 conductances give rise to excess correlations that cannot be compensated for by synaptic scaling or homeostatic modulation of passive membrane properties. In contrast, modulation of Kv7 activation parameters consistent with pharmacological treatments for certain hyperactivity disorders can restore normal firing rates and spiking correlations. Our results provide key insights into how regulation of a ubiquitous potassium channel class can control the coordination of population spiking activity. . M currents have slow activation kinetics, lack inactivation dynamics, and decrease overall cellular excitability (Aiken et al. 1995;Gu et al. 2005;Higgs et al. 2007;Lawrence et al. 2006;Peters et al. 2005). M currents are due to heteromeric channels composed of Kv7.2/3 and Kv7.3/5 subunits that are encoded by the KCNQ gene family (Wang et al. 1998;Selyanko et al. 2001;Peters et al. 2005). Dysfunction of Kv7 channels is related to a number of disease: shifts in Kv7 activation have been associated with tinnitus (Li et al. 2013), mutations involved in peripheral nerve hyperexcitability decrease Kv7 surface expression (Wuttke et al. 2007), and changes in both voltage-sensing and surface expression have been related to neonatal epilepsy (Soldovieri et al. 2006). Kv7 mutations are also associated with the most common childhood epilepsy condition, rolandic epilepsy (Coppola et al. 2003;Neubauer et al. 2008). Despite the evidence of reduced Kv7 activation in tinnitus, chronic pain, and epilepsy, there lacks a coherent mechanistic theory for how Kv7 channels contribute to physiological signatures of such disease states.Two common neural correlates of tinnitus and epilepsy are elevated firing rates and excess spike train synchro...

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