Selective attenuation of Ether-a-go-go related K+ currents by endogenous acetylcholine reduces spike-frequency adaptation and network correlation.

Edward D Cui,Ben W Strowbridge

doi:10.7554/elife.44954

Abstract

Most neurons do not simply convert inputs into firing rates. Instead, moment-to-moment firing rates reflect interactions between synaptic inputs and intrinsic currents. Few studies investigated how intrinsic currents function together to modulate output discharges and which of the currents attenuated by synthetic cholinergic ligands are actually modulated by endogenous acetylcholine (ACh). In this study we optogenetically stimulated cholinergic fibers in rat neocortex and find that ACh enhances excitability by reducing Ether-à-go-go Related Gene (ERG) K+ current. We find ERG mediates the late phase of spike-frequency adaptation in pyramidal cells and is recruited later than both SK and M currents. Attenuation of ERG during coincident depolarization and ACh release leads to reduced late phase spike-frequency adaptation and persistent firing. In neuronal ensembles, attenuating ERG enhanced signal-to-noise ratios and reduced signal correlation, suggesting that these two hallmarks of cholinergic function in vivo may result from modulation of intrinsic properties.

Highlights

Understanding how modulatory systems function to govern neural circuits is a fundamental question in neuroscience
We assayed the effects of endogenous ACh release in 154 L5 regular spiking neocortical pyramidal cells in P35-45 rats injected with AAV-ChR2 in the nucleus basalis (NB), a major source of cholinergic input to the neocortex in both rodents (Mesulam et al, 1983a) and primates (Mesulam et al, 1983b)
While our findings showed that Ether-a -go-go Related Gene (ERG) antagonists occlude the increase in neuronal excitability triggered by endogenous ACh, previous work using bath application of cholinergic receptor agonists such as CCh have identified other K+ channel targets of mAChR-driven modulation (Suh and Hille, 2002, Buchanan et al, 2010, Hirdes et al, 2004) that likely contribute to spike frequency adaptation (SFA) in cortical pyramidal cells

Summary

Introduction

Understanding how modulatory systems function to govern neural circuits is a fundamental question in neuroscience. Studies of circuit activity during tasks that promote ACh release demonstrate more complex changes than expected from a uniform increase in neuronal excitability, including network desynchronization (Metherate et al, 1992, Kalmbach et al, 2012, Pinto et al, 2013, increasing signal-to-noise ratios (SNR, Zinke et al, 2006, Sato et al, 1987, Minces et al, 2017), and reducing correlation of activity levels between neurons (Goard and Dan, 2009, Minces et al, 2017) Together, these effects enable cholinergic modulation to improve visual discrimination (Pinto et al, 2013), enhance sensory coding (Goard and Dan, 2009) and influence attention (Steinmetz et al, 2000, Briggs et al, 2013) and working memory (Goard and Dan, 2009, Ballinger et al, 2016). Previous work has identified large set of outward and inward currents that could explain the increase in excitability traditionally found with cholinergic stimulation

Methods

Results

Conclusion