A Calcium-Dependent Plasticity Rule for HCN Channels Maintains Activity Homeostasis and Stable Synaptic Learning

Proc. Natl. Acad. Sci. U.S.A.

2014

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239

The maintenance of ion channel homeostasis, or channelostasis, is a complex puzzle in neurons with extensive dendritic arborization, encompassing a combinatorial diversity of proteins that encode these channels and their auxiliary subunits, their localization profiles, and associated signaling machinery. Despite this, neurons exhibit amazingly stereotypic, topographically continuous maps of several functional properties along their active dendritic arbor. Here, we asked whether the membrane composition of neurons, at the level of individual ion channels, is constrained by this structural requirement of sustaining several functional maps along the same topograph. We performed global sensitivity analysis on morphologically realistic conductance-based models of hippocampal pyramidal neurons that coexpressed six well-characterized functional maps along their trunk. We generated randomized models by varying 32 underlying parameters and constrained these models with quantitative experimental measurements from the soma and dendrites of hippocampal pyramidal neurons. Analyzing valid models that satisfied experimental constraints on all six functional maps, we found topographically analogous functional maps to emerge from disparate model parameters with weak pairwise correlations between parameters. Finally, we derived a methodology to assess the contribution of individual channel conductances to the various functional measurements, using virtual knockout simulations on the valid model population. We found that the virtual knockout of individual channels resulted in variable, measurementand location-specific impacts across the population. Our results suggest collective channelostasis as a mechanism behind the robust emergence of analogous functional maps and have significant ramifications for the localization and targeting of ion channels and enzymes that regulate neural coding and homeostasis. C hannel homeostasis, or channelostasis, refers to the regulation of the density, kinetics, voltage dependence, binding interactions, and the subcellular localization of individual ion channel types within a given cell [compared to proteostasis (1)]. Hippocampal CA1 pyramidal neurons are endowed with complex dendritic morphology and express numerous voltage-gated ion channels (VGICs), which govern critical neuronal functions across their somatodendritic arbor (2-6). Channelostasis in such neurons is an exceptionally complex puzzle, given the enormous morphological and molecular complexities accompanied by a myriad of subcellular channel localization profiles, resulting in an immense combinatorial diversity in channel expression profiles (4, 7-11). A further conundrum that compounds this complex puzzle is that neurons, despite these underlying complexities, exhibit amazingly regular gradients in several functional properties that manifest as maps along a continuous neuronal topograph (3). The coexistence of all these topographically continuous maps along the same neuronal topograph is mediated by intricately regulated subcellular l...

Section: Discussionmentioning

confidence: 99%

Homeostasis of functional maps in active dendrites emerges in the absence of individual channelostasis

Rathour

Proc. Natl. Acad. Sci. U.S.A.

2014

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239

“…The location-dependent expression (Kole et al 2006;Lorincz et al 2002;Magee 1998;Williams and Stuart 2000) and plasticity of HCN channels (Campanac et al 2008;Fan et al 2005;Johnston 2008, 2007;Shah 2014;Shah et al 2010;Wang et al 2003), in conjunction with this ability to alter subthreshold response dynamics, have led to several postulates on their physiological roles. The postulated roles for HCN channels include those as regulators of location-dependent optimal filters (Kalmbach et al 2013;Narayanan and Johnston 2007), of temporal summation and temporal coding (Magee 1998(Magee , 2000Magee and Cook 2000;Narayanan and Johnston 2008;Wang 2010), and of transfer impedance amplitude and phase (Hu et al 2009;Ulrich 2002;Vaidya and Johnston 2013), and as mediators of spectral selectivity in spike initiation dynamics (Das and Narayanan 2014) and of metaplasticity by altering synaptic plasticity rules (Honnuraiah and Narayanan 2013;Nolan et al 2004). Against this wide array of potential roles, it is imperative that HCN channels are not analyzed only from a limited perspective of how they alter RMP and excitability.…”

Section: Discussionmentioning

confidence: 99%

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

Mishra

Journal of Neurophysiology

2015

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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.

“…However, there are several lines of theoretical and experimental evidence, spanning several synaptic and intrinsic components as candidate mechanisms, for concurrent emergence of encoding, stability and activity homeostasis. These lines of evidence also argue for significant advantages when encoding, homeostasis and stability mechanisms are concurrent (Anirudhan and Narayanan, 2015;Honnuraiah and Narayanan, 2013;Ibata et al, 2008;Johnston and Narayanan, 2008;Johnston, 2007, 2010;Nelson and Turrigiano, 2008;Triesch, 2007;Turrigiano, 2011;Turrigiano, 2008Turrigiano, , 2017Zenke et al, 2017).…”

Section: Degeneracy In Metaplasticity and In Maintaining Stability Ofmentioning

confidence: 99%

“…Even with reference to individual neurons, the literature has defined several forms of homeostasis, with popular measures involving neuronal firing rate, cytosolic calcium or excitation-inhibition balance (Gjorgjieva et al, 2016;Hengen et al, 2016;Honnuraiah and Narayanan, 2013;Nelson and Turrigiano, 2008;Siegel et al, 1994;Srikanth and Narayanan, 2015;Turrigiano, 2011;Turrigiano, 1999Turrigiano, , 2008Turrigiano and Nelson, 2004;Yizhar et al, 2011). In addition, despite perpetual changes in afferent activity under in vivo conditions (Buzsaki, 1986(Buzsaki, , 1989(Buzsaki, , 2002(Buzsaki, , 2006Buzsaki et al, 1992;Csicsvari et al, 1999;English et al, 2014;Grosmark et al, 2012;Louie and Wilson, 2001;Mizuseki et al, 2011;Montgomery et al, 2008;Srikanth and Narayanan, 2015;Tononi and Cirelli, 2006;Wilson and McNaughton, 1994;Ylinen et al, 1995a), specific neuronal subtypes maintain distinct functional signatures, say in terms of their excitability or oscillatory or frequency selectivity measurements, that are different from other neuronal subtypes even in the same brain region Shepherd, 2002, 2005;Johnston, 2007, 2008;Pike et al, 2000;Spruston, 2008;Zemankovics et al, 2010).…”

Section: Dissociation Between Different Forms Of Homeostasismentioning

confidence: 99%

Degeneracy in hippocampal physiology and plasticity

Rathour

2017

Preprint

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Degeneracy, defined as the ability of structurally disparate elements to perform analogous function, has largely been assessed from the perspective of maintaining robustness of physiology or plasticity. How does the framework of degeneracy assimilate into an encoding system where the ability to change is an essential ingredient for storing new incoming information? Could degeneracy maintain the balance between the apparently contradictory goals of the need to change for encoding and the need to resist change towards maintaining homeostasis? In this review, we explore these fundamental questions with the mammalian hippocampus as an example encoding system. We systematically catalog lines of evidence, spanning multiple scales of analysis, that demonstrate the expression of degeneracy in hippocampal physiology and plasticity. We assess the potential of degeneracy as a framework to achieve encoding and homeostasis without cross-interferences, and postulate that multiscale parametric and interactional complexity could establish disparate routes towards accomplishing these conjoint goals. These disparate routes then provide several degrees of freedom to the encodinghomeostasis system in accomplishing its tasks in an input-and state-dependent manner. Finally, the expression of degeneracy spanning multiple scales offers an ideal reconciliation to several outstanding controversies, through the recognition that the seemingly contradictory disparate observations are merely alternate routes that the system might recruit towards accomplishment of its goals. Juxtaposed against the ubiquitous prevalence of degeneracy and its strong links to evolution, it is perhaps apt to add a corollary to Theodosius Dobzhansky's famous quote and state "nothing in physiology makes sense except in the light of degeneracy".peer-reviewed)