High-conductance states and A-type K⁺ channels are potential regulators of the conductance-current balance triggered by HCN channels

Abstract

An increase in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel conductance reduces input resistance, whereas the consequent increase in the inward h current depolarizes the membrane. This results in a delicate and unique conductance-current balance triggered by the expression of HCN channels. In this study, we employ experimentally constrained, morphologically realistic, conductance-based models of hippocampal neurons to explore certain aspects of this conductance-current balance. First, we found that the inclusion of an experimentally determined gradient in A-type K(+) conductance, but not in M-type K(+) conductance, tilts the HCN conductance-current balance heavily in favor of conductance, thereby exerting an overall restorative influence on neural excitability. Next, motivated by the well-established modulation of neuronal excitability by synaptically driven high-conductance states observed under in vivo conditions, we inserted thousands of excitatory and inhibitory synapses with different somatodendritic distributions. We measured the efficacy of HCN channels, independently and in conjunction with other channels, in altering resting membrane potential (RMP) and input resistance (Rin) when the neuron received randomized or rhythmic synaptic bombardments through variable numbers of synaptic inputs. We found that the impact of HCN channels on average RMP, Rin, firing frequency, and peak-to-peak voltage response was severely weakened under high-conductance states, with the impinging synaptic drive playing a dominant role in regulating these measurements. Our results suggest that the debate on the role of HCN channels in altering excitability should encompass physiological and pathophysiological neuronal states under in vivo conditions and the spatiotemporal interactions of HCN channels with other channels.

Computational models of O-LM cells are recruited by low or high theta frequency inputs depending on h-channel distributions

“…For instance, computational investigations using multi-compartment models have suggested that, in CA1 pyramidal neurons, interactions between h-channels and TASK-like potassium leak channels could explain paradoxical findings such as membrane depolarization after h-channel block (Migliore and Migliore, 2012). Other modelling work with CA1 pyramidal neurons has predicted that A-type potassium channels modulate the efficacy of the h-current balance between conductance and current, which exhibit counteracting effects of decreasing input resistance and depolarizing the membrane potential, respectively (Mishra and Narayanan, 2015). It is thus reasonable to also consider dendritic functional maps for different inhibitory cell types, and specifically O-LM cells which, to our knowledge, has not been done to date.…”

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

“…S1 A-C). Because of the domination of the underlying rhythmic high-conductance state (36), the LFP amplitudes across recording sites were not significantly different with the insertion of HCN channels. However, the incorporation of HCN channels introduced a significant location-dependent phase lead in the LFPs across all recording sites, when compared with corresponding LFPs computed in the absence of HCN channels ( Fig.…”

Degeneracy in hippocampal physiology and plasticity

“…2-3). First, there is significant degeneracy in the emergence of neurophysiological properties, where disparate combinations of channels could come together to elicit similar functional properties Narayanan, 2014, 2015;Drion et al, 2015;Foster et al, 1993;Gjorgjieva et al, 2016;Goldman et al, 2001;Grashow et al, 2010;Marder, 2011;Marder and Goaillard, 2006;Marder and Taylor, 2011;Mishra and Narayanan, 2015;Rathour et al, 2016;Narayanan, 2012a, b, 2014;Taylor et al, 2009). Second, the dependence of different physiological properties on distinct peer-reviewed) is the author/funder.…”

“…16, 2017; in regulating intrinsic properties and their location-dependent characteristics, especially in electrotonically non-compact hippocampal pyramidal neurons (Dhupia et al, 2015;Golding et al, 2005;Krichmar et al, 2002;Mainen and Sejnowski, 1996;Narayanan and Chattarji, 2010;Spruston et al, 1994;Spruston et al, 1993), and could significantly contribute to degeneracy in the emergence of single-neuron physiology. Finally, depending on the localization profiles and voltage-dependent properties of different channels they may or may not spatiotemporally interact (Migliore and Migliore, 2012;Mishra and Narayanan, 2015;Rathour and Narayanan, 2012b).…”