Quantitative interactions between the A‐type K⁺ current and inositol trisphosphate receptors regulate intraneuronal Ca²⁺ waves and synaptic plasticity

Abstract

Key points• Active calcium signal propagation occurs when an initial calcium trigger elicits calcium release through endoplasmic reticulum (ER) receptors. A high concentration of the calcium trigger in thin-calibre dendrites would suppress release of calcium through hippocampal inositol trisphosphate receptors (InsP 3 Rs).• Could the high-density expression of A-type K + channels in thin-calibre dendrites be a mechanism for inhibiting this suppression, thereby restoring the utility of the ER as a substrate for active calcium propagation?• Quantitative analyses involving experimentally constrained models reveal a bell-shaped dependence of calcium released through InsP 3 Rs on the A-type K + channel density, during the propagation of a calcium wave.• A-type K + channels regulated the relative contribution of ER calcium to the induction of synaptic plasticity in the presence of model metabotropic glutamate receptors.• These results identify a novel form of interaction between active dendrites and the ER membrane and suggest that A-type K + channels are ideally placed for inhibiting the suppression of InsP 3 Rs in thin-calibre dendrites.Abstract The A-type potassium current has been implicated in the regulation of several physiological processes. Here, we explore a role for the A-type potassium current in regulating the release of calcium through inositol trisphosphate receptors (InsP 3 R) that reside on the endoplasmic reticulum (ER) of hippocampal pyramidal neurons. To do this, we constructed morphologically realistic, conductance-based models equipped with kinetic schemes that govern several calcium signalling modules and pathways, and constrained the distributions and properties of constitutive components by experimental measurements from these neurons. Employing these models, we establish a bell-shaped dependence of calcium release through InsP 3 Rs on the density of A-type potassium channels, during the propagation of an intraneuronal calcium wave initiated through established protocols. Exploring the sensitivities of calcium wave initiation and propagation to several underlying parameters, we found that ER calcium release critically depends on dendritic diameter and that wave initiation occurred at branch points as a consequence of a high surface area to volume ratio of oblique dendrites. Furthermore, analogous to the role of A-type potassium channels in regulating spike latency, we found that an increase in the density of A-type potassium channels led to increases in the latency and the temporal spread of a propagating calcium wave. Next, we incorporated kinetic models for the metabotropic glutamate receptor (mGluR) signalling components and a calcium-controlled plasticity rule into our model and demonstrate that the presence of mGluRs induced a leftward shift in a Bienenstock-Cooper-Munro-like synaptic plasticity profile. Finally, we show that the A-type potassium current could regulate the relative contribution of ER calcium to synaptic plasticity induced either through 900 pulses of various stimulus frequ...

Analogous Synaptic Plasticity Profiles Emerge from Disparate Channel Combinations

“…The current through the NMDA receptor, as a function of voltage and time, was dependent on three ions: sodium, potassium, and calcium. Consequently, as per the GoldmanHodgkin-Katz convention (Goldman, 1943;Hodgkin and Katz, 1949;Mayer and Westbrook, 1987;Canavier, 1999;Narayanan and Johnston, 2010;Ashhad and Narayanan, 2013;Honnuraiah and Narayanan, 2013):…”

“…1A), with the default value of NMDAR:AMPAR ratio set at 1.5. The kinetics of AMPA and NMDA receptor currents were adopted from previous literature (Narayanan Ashhad and Narayanan, 2013;Honnuraiah and Narayanan, 2013) and are detailed below. The current through the NMDA receptor, as a function of voltage and time, was dependent on three ions: sodium, potassium, and calcium.…”

“…where a is a normalization constant, making sure that 0 Յ s(t) Յ 1, d is the decay time constant, r is rise time, with r ϭ 5 ms, and default d ϭ 50 ms (Dingledine et al, 1999;Narayanan and Johnston, 2010;Ashhad and Narayanan, 2013;Honnuraiah and Narayanan, 2013). Current through the AMPA receptor was modeled as the sum of currents carried by these sodium and potassium ions:…”

“…Although the impact of certain voltagegated ion channels on synaptic plasticity profiles has been quantitatively assessed (Narayanan and Johnston, 2010;Ashhad and Narayanan, 2013;Honnuraiah and Narayanan, 2013), the role of interactions between several coexpressing dendritic ion channels in inducing metaplasticity or how such interactions contribute or hamper the maintenance of plasticity profile homeostasis have not been analyzed. Further, plasticity during learning and pathology also span intrinsic components apart from changes in synaptic structures (Turrigiano et al, 1994;Johnston et al, 2003;Frick and Johnston, 2005;Magee and Johnston, 2005;Bernard et al, 2007;Kim and Linden, 2007;Johnston and Narayanan, 2008;Sjöström et al, 2008;Mozzachiodi and Byrne, 2010;Remy et al, 2010;Shah et al, 2010;Turrigiano, 2011;Lee and Jan, 2012;Narayanan and Johnston, 2012;Brager and Johnston, 2014;Shah, 2014).…”

“…We first analyzed the sensitivity of the BCM-like plasticity profile on several combinations of the T-(CaT) and R-type (CaR) calcium, and the small conductance calcium-activated potassium (SK) channels, all of which have been implicated in regulating synaptic plasticity (Golding et al, 2002;Yasuda et al, 2003;Takahashi and Magee, 2009;. Next, we turned to the powerful global sensitivity analysis Marder and Taylor, 2011; on seven different ion channels to expand interactions among ion channels beyond pairwise interactions (Narayanan and Johnston, 2010;Ashhad and Narayanan, 2013;Honnuraiah and Narayanan, 2013), and assessed the role of cross-channel interactions in altering synaptic plasticity profiles. Finally, we used the virtual knock-out model (VKM) analyses technique introduced in (Rathour and Narayanan, 2014) to assess the relative impact of each ion channel on the synaptic plasticity profile.…”