HCN channels enhance spike phase coherence and regulate the phase of spikes and LFPs in the theta-frequency range

Abstract

What are the implications for the existence of subthreshold ion channels, their localization profiles, and plasticity on local field potentials (LFPs)? Here, we assessed the role of hyperpolarizationactivated cyclic-nucleotide-gated (HCN) channels in altering hippocampal theta-frequency LFPs and the associated spike phase. We presented spatiotemporally randomized, balanced theta-modulated excitatory and inhibitory inputs to somatically aligned, morphologically realistic pyramidal neuron models spread across a cylindrical neuropil. We computed LFPs from seven electrode sites and found that the insertion of an experimentally constrained HCN-conductance gradient into these neurons introduced a location-dependent lead in the LFP phase without significantly altering its amplitude. Further, neurons fired action potentials at a specific theta phase of the LFP, and the insertion of HCN channels introduced large lags in this spike phase and a striking enhancement in neuronal spike-phase coherence. Importantly, graded changes in either HCN conductance or its half-maximal activation voltage resulted in graded changes in LFP and spike phases. Our conclusions on the impact of HCN channels on LFPs and spike phase were invariant to changes in neuropil size, to morphological heterogeneity, to excitatory or inhibitory synaptic scaling, and to shifts in the onset phase of inhibitory inputs. Finally, we selectively abolished the inductive lead in the impedance phase introduced by HCN channels without altering neuronal excitability and found that this inductive phase lead contributed significantly to changes in LFP and spike phase. Our results uncover specific roles for HCN channels and their plasticity in phase-coding schemas and in the formation and dynamic reconfiguration of neuronal cell assemblies.L ocal field potentials (LFPs) have been largely believed to be a reflection of the synaptic drive that impinges on a neuron. In recent experimental and modeling studies, there has been a lot of debate on the source and spatial extent of LFPs (1-9). However, most of these studies have used neurons with passive dendrites in their models and/or have largely focused on the contribution of spike-generating conductances to LFPs (7,8,10,11). Despite the widely acknowledged regulatory roles of subthreshold-activated ion channels and their somatodendritic gradients in the physiology and pathophysiology of synapses and neurons (12-17), the implications for their existence on LFPs and neuronal spike phase have surprisingly remained unexplored. This lacuna in LFP analysis is especially striking because local and widespread plasticity of these channels has been observed across several physiological and pathological conditions, translating to putative roles for these channels in neural coding, homeostasis, disease etiology and remedies, learning, and memory (16,(18)(19)(20)(21)(22)(23).In this study, we focus on the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that mediate the h current (I h ) in regulating LFPs and ...

Active subthreshold dendritic conductances shape the local field potential

“…; Reimann et al . ; Sinha & Narayanan, ). For passive dendrites the key factor in determining the magnitude and spread of the population LFP was found to be the amount of correlation between the numerous synaptic inputs to the population (Lindén et al .…”

“…; Taxidis et al . ; Sinha and Narayanan, ). Neurons express a variety of active conductances that are distributed in specific ways across both soma and dendrites (Stuart et al .…”

Degeneracy in hippocampal physiology and plasticity

“…A similar analysis, in terms of disparate underlying sources and mechanisms, holds for gamma frequency oscillations that are observed in the hippocampus as well (Buzsaki and Wang, 2012;Colgin, 2016;Colgin and Moser, 2010;Csicsvari et al, 2003;Wang, 2010;Wang and Buzsaki, 1996). In addition, apart from synaptic contributions to the LFPs, it is now clear that return transmembrane currents from sub-and supra-threshold somatodendritic ion channels also significantly alter the LFP in terms of their frequency content, amplitude and phase Einevoll et al, 2013;Ness et al, 2016;Reimann et al, 2013;Schomburg et al, 2012;Sinha and Narayanan, 2015;Taxidis et al, 2015). In addition, several mechanisms such ephaptic coupling, heterogeneous extracellular resistivity, glial and axonal transmembrane mechanisms also contribute and regulate local field potentials, resulting in a complexity that spans almost all parameters of the local network Einevoll et al, 2013;Kajikawa and Schroeder, 2011;Katzner et al, 2009;Linden et al, 2011).…”

“…16, 2017; From the complexity involved in the generation and regulation of hippocampal LFPs, with several brain regions and several constitutive network components contributing to their emergence, it is easy to discern that similar LFP patterns could be achieved through non-unique combinations of disparate components. Irrespective of whether it is the manifestation of an oscillatory pattern in a given frequency range (Buzsaki, 2002;Buzsaki and Wang, 2012;Colgin, 2013;Colgin and Moser, 2010;Csicsvari et al, 2003), or the emergence of sharp wave ripples (Buzsaki, 2015;English et al, 2014;Taxidis et al, 2015), or the emergence of resonance in the LFP power spectral density (Ness et al, 2016), or achieving a given phase of single-neuron firing with reference to an LFP oscillation (Sinha and Narayanan, 2015), the routes are several and involve several disparate structural components. Thus, there is significant degeneracy in the mechanisms that mediate and regulate local field potentials, implying that extreme caution should be exercised in making one-to-one relationships between constitutive components and specific aspects of LFP recordings Einevoll et al, 2013;Kajikawa and Schroeder, 2011;Katzner et al, 2009;Linden et al, 2011).…”

“…The expression profiles of several channels and receptors control the overall excitability of a neuron (Sec. 2.2), and there are several mechanisms that regulate the phase of intracellular voltage oscillations with reference to an external reference or to the overall afferent current (Geisler et al, 2010;Geisler et al, 2007;Harvey et al, 2009;Narayanan and Johnston, 2008;Rathour et al, 2016;Narayanan, 2012a, 2014;Sinha and Narayanan, 2015;Skaggs et al, 1996). Together, similar rate and phase spatial codes in a neuron could be achieved through disparate combinations of constituent components, and several neurons could encode for the same place field with distinct combinations of these mechanisms.…”