Transient potassium channels augment degeneracy in hippocampal active dendritic spectral tuning

Hippocampal pyramidal neurons express an intraneuronal map of spectral tuning mediated by hyperpolarization-activated cyclic-nucleotide-gated nonspecific-cation channels. Modeling studies have predicted a critical regulatory role for A-type potassium (KA) channels towards augmenting functional robustness of this map. To test this, we performed patch-clamp recordings from soma and dendrites of rat hippocampal pyramidal neurons, and measured spectral tuning before and after blocking KA channels using two structurally distinct pharmacological agents. Consistent with computational predictions, we found that blocking KA channels resulted in a significant reduction in resonance frequency and significant increases in input resistance, impedance amplitude and action-potential firing frequency across the somato-apical trunk. Furthermore, across all measured locations, blocking KA channels enhanced temporal summation of postsynaptic potentials and critically altered the impedance phase profile, resulting in a significant reduction in total inductive phase. Finally, pair-wise correlations between intraneuronal percentage changes (after blocking KA channels) in different measurements were mostly weak, suggesting differential regulation of different physiological properties by KA channels. Our results unveil a pivotal role for fast transient channels in regulating theta-frequency spectral tuning and intrinsic phase response, and suggest that degeneracy with reference to several coexisting functional maps is mediated by cross-channel interactions across the active dendritic arbor.

Zervamicins, a structurally characterised peptide model for membrane ion channels

Voltage dependent membrane channels are formed by the zervamicins, a group of α-aminoisobutyric acid containing peptides. The role of polar residues like Thr, Gln and Hyp in promoting helical bundle formation is established by dramatically reduced channel lifetimes for a synthetic apolar analog. Crystal structures of Leu1-zervamicin reveal association of bent helices. Polar contacts between convex faces result in an ‘hour glass’ like arrangement of an aqueous channel with a central constriction. The structure suggests that gating mechanisms may involve movement of the Gln11 carboxamide group. Gln3 may play a role in modulating the size of the channel mouth.

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

Key points center dot 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 (InsP3Rs). center dot 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? center dot Quantitative analyses involving experimentally constrained models reveal a bell-shaped dependence of calcium released through InsP3Rs on the A-type K+ channel density, during the propagation of a calcium wave. center dot 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. center dot 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 InsP3Rs 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 (InsP3R) 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 InsP3Rs on the density ofA-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 ofA-type potassium channels in regulating spike latency, we found that an increase in the density ofA-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 thatthe presence of mGluRs induced a leftward shift in a BienenstockCooperMunro-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 frequencies or through theta burst stimulation. Our results establish a novel form of interaction between active dendrites and the ER membrane, uncovering a powerful mechanism that could regulate biophysical/biochemical signal integration and steer the spatiotemporal spread of signalling microdomains through changes in dendritic excitability.

Active dendrites mediate stratified gamma-range coincidence detection in hippocampal model neurons

Hippocampal pyramidal neurons exhibit gamma-phase preference in their spikes, selectively route inputs through gamma frequency multiplexing and are considered part of gamma-bound cell assemblies. How do these neurons exhibit gamma-frequency coincidence detection capabilities, a feature that is essential for the expression of these physiological observations, despite their slow membrane time constant? In this conductance-based modelling study, we developed quantitative metrics for the temporal window of integration/coincidence detection based on the spike-triggered average (STA) of the neuronal compartment. We employed these metrics in conjunction with quantitative measures for spike initiation dynamics to assess the emergence and dependence of coincidence detection and STA spectral selectivity on various ion channel combinations. We found that the presence of resonating conductances (hyperpolarization-activated cyclic nucleotide-gated or T-type calcium), either independently or synergistically when expressed together, led to the emergence of spectral selectivity in the spike initiation dynamics and a significant reduction in the coincidence detection window (CDW). The presence of A-type potassium channels, along with resonating conductances, reduced the STA characteristic frequency and broadened the CDW, but persistent sodium channels sharpened the CDW by strengthening the spectral selectivity in the STA. Finally, in a morphologically precise model endowed with experimentally constrained channel gradients, we found that somatodendritic compartments expressed functional maps of strong theta-frequency selectivity in spike initiation dynamics and gamma-range CDW. Our results reveal the heavy expression of resonating and spike-generating conductances as the mechanism underlying the robust emergence of stratified gamma-range coincidence detection in the dendrites of hippocampal and cortical pyramidal neurons.

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

Theoretical and computational frameworks for synaptic plasticity and learning have a long and cherished history, with few parallels within the well-established literature for plasticity of voltage-gated ion channels. In this study, we derive rules for plasticity in the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and assess the synergy between synaptic and HCN channel plasticity in establishing stability during synaptic learning. To do this, we employ a conductance-based model for the hippocampal pyramidal neuron, and incorporate synaptic plasticity through the well-established Bienenstock-Cooper-Munro (BCM)-like rule for synaptic plasticity, wherein the direction and strength of the plasticity is dependent on the concentration of calcium influx. Under this framework, we derive a rule for HCN channel plasticity to establish homeostasis in synaptically-driven firing rate, and incorporate such plasticity into our model. In demonstrating that this rule for HCN channel plasticity helps maintain firing rate homeostasis after bidirectional synaptic plasticity, we observe a linear relationship between synaptic plasticity and HCN channel plasticity for maintaining firing rate homeostasis. Motivated by this linear relationship, we derive a calcium-dependent rule for HCN-channel plasticity, and demonstrate that firing rate homeostasis is maintained in the face of synaptic plasticity when moderate and high levels of cytosolic calcium influx induced depression and potentiation of the HCN-channel conductance, respectively. Additionally, we show that such synergy between synaptic and HCN-channel plasticity enhances the stability of synaptic learning through metaplasticity in the BCM-like synaptic plasticity profile. Finally, we demonstrate that the synergistic interaction between synaptic and HCN-channel plasticity preserves robustness of information transfer across the neuron under a rate-coding schema. Our results establish specific physiological roles for experimentally observed plasticity in HCN channels accompanying synaptic plasticity in hippocampal neurons, and uncover potential links between HCN-channel plasticity and calcium influx, dynamic gain control and stable synaptic learning.

Information Theoretic Results for Three-User Cognitive Channels

In this paper, we introduce the three-user cognitive radio channels with asymmetric transmitter cooperation, and derive achievable rate regions under several scenarios depending on the type of cooperation and decoding capability at the receivers. Two of the most natural cooperation mechanisms for the three-user channel are considered here: cumulative message sharing (CMS) and primary-only message sharing (PMS). In addition to the message sharing mechanism, the achievable rate region is critically dependent on the decoding capability at the receivers. Here, we consider two scenarios for the decoding capability, and derive an achievable rate region for each one of them by employing a combination of superposition and Gel'fand-Pinsker coding techniques. Finally, to provide a numerical example, we consider the Gaussian channel model to plot the rate regions. In terms of achievable rates, CMS turns out to be a better scheme than PMS. However, the practical aspects of implementing such message-sharing schemes remain to be investigated.

Theory of the effects of destruction of localization by inelastic scattering in the resistivity of pure thin potassium wires

Measurements of the electrical resistivity of thin potassium wires at temperatures near 1 K have revealed a minimum in the resistivity as a function of temperature. By proposing that the electrons in these wires have undergone localization, albeit with large localization length, and that inelastic-scattering events destroy the coherence of that state, we can explain both the magnitude and shape of the temperature-dependent resistivity data. Localization of electrons in these wires is to be expected because, due to the high purity of the potassium, the elastic mean free path is comparable to the diameters of the thinnest samples, making the Thouless length lT (or inelastic diffusion length) much larger than the diameter, so that the wire is effectively one dimensional. The inelastic events effectively break the wire into a series of localized segments, whose resistances can be added to obtain the total resistance of the wire. The ensemble-averaged resistance for all possible segmented wires, weighted with a Poisson distribution of inelastic-scattering lengths along the wire, yields a length dependence for the resistance that is proportional to [L3/lin(T)], provided that lin(T)?L, where L is the sample length and lin(T) is some effective temperature-dependent one-dimensional inelastic-scattering length. A more sophisticated approach using a Poisson distribution in inelastic-scattering times, which takes into account the diffusive motion of the electrons along the wire through the Thouless length, yields a length- and temperature-dependent resistivity proportional to (L/lT)4 under appropriate conditions. Inelastic-scattering lifetimes are inferred from the temperature-dependent bulk resistivities (i.e., those of thicker, effectively three-dimensional samples), assuming that a minimum amount of energy must be exchanged for a collision to be effective in destroying the phase coherence of the localized state. If the dominant inelastic mechanism is electron-electron scattering, then our result, given the appropriate choice of the channel number parameter, is consistent with the data. If electron-phason scattering were of comparable importance, then our results would remain consistent. However, the inelastic-scattering lifetime inferred from bulk resistivity data is too short. This is because the electron-phason mechanism dominates in the inelastic-scattering rate, although the two mechanisms may be of comparable importance for the bulk resistivity. Possible reasons why the electron-phason mechanism might be less effective in thin wires than in bulk are discussed.

Phase modification of ammonium nitrate by potassium salts

Modification of the room temperature phase (IV-III) of ammonium nitrate (AN) has been attempted using a variety of potassium salts namely, KF, KCl, KI, KNO3, K2CO3, K2SO4, KSCN and K2Cr2O7. No phase transition was observed when AN containing 1-2% by mass of these potassium salts is heated from room temperature (25 degrees C) onwards in DTA and DSC scans, but the linear expansion due to phase transition was still observable in TMA measurements. Complete arrest of the linear expansion occurs only when a higher concentration of the additive is used. Similarly, in thermal cycling experiments, complete phase modification in the temperature range -80 to 100 degrees C occurs only with a higher percentage of the potassium salt. The extent of modification, however, is found to be dependent both on the concentration, and the type of the anion. Potassium dichromate when used as an additive modifies the phase as well as the decomposition pattern of AN.

A naturally occurring amino acid substitution in the voltage-dependent sodium channel selectivity filter affects channel gating

The pore of sodium channels contains a selectivity filter made of 4 amino acids, D/E/K/A. In voltage sensitive sodium channel (Nav) channels from jellyfish to human the fourth amino acid is Ala. This Ala, when mutated to Asp, promotes slow inactivation. In some Nav channels of pufferfishes, the Ala is replaced with Gly. We studied the biophysical properties of an Ala-to-Gly substitution (A1529G) in rat Nav1.4 channel expressed in Xenopus oocytes alone or with a beta 1 subunit. The Ala-to-Gly substitution does not affect monovalent cation selectivity and positively shifts the voltage-dependent inactivation curve, although co-expression with a beta 1 subunit eliminates the difference between A1529G and WT. There is almost no difference in channel fast inactivation, but the beta 1 subunit accelerates WT current inactivation significantly more than it does the A1529G channels. The Ala-to-Gly substitution mainly influences the rate of recovery from slow inactivation. Again, the beta 1 subunit is less effective on speeding recovery of A1529G than the WT. We searched Nav channels in numerous databases and noted at least four other independent Ala-to-Gly substitutions in Nav channels in teleost fishes. Thus, the Ala-to-Gly substitution occurs more frequently than previously realized, possibly under selection for alterations of channel gating.

Active Dendrites Regulate Spectral Selectivity in Location-Dependent Spike Initiation Dynamics of Hippocampal Model Neurons

How does the presence of plastic active dendrites in a pyramidal neuron alter its spike initiation dynamics? To answer this question, we measured the spike-triggered average (STA) from experimentally constrained, conductance-based hippocampal neuronal models of various morphological complexities. We transformed the STA computed from these models to the spectral and the spectrotemporal domains and found that the spike initiation dynamics exhibited temporally localized selectivity to a characteristic frequency. In the presence of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, the STA characteristic frequency strongly correlated with the subthreshold resonance frequency in the theta frequency range. Increases in HCN channel density or in input variance increased the STA characteristic frequency and its selectivity strength. In the absence of HCN channels, the STA exhibited weak delta frequency selectivity and the characteristic frequency was related to the repolarization dynamics of the action potentials and the recovery kinetics of sodium channels from inactivation. Comparison of STA obtained with inputs at various dendritic locations revealed that nonspiking and spiking dendrites increased and reduced the spectrotemporal integration window of the STA with increasing distance from the soma as direct consequences of passive filtering and dendritic spike initiation, respectively. Finally, the presence of HCN channels set the STA characteristic frequency in the theta range across the somatodendritic arbor and specific STA measurements were strongly related to equivalent transfer-impedance-related measurements. Our results identify explicit roles for plastic active dendrites in neural coding and strongly recommend a dynamically reconfigurable multi-STA model to characterize location-dependent input feature selectivity in pyramidal neurons.

Depression biased non-Hebbian spike-timing-dependent synaptic plasticity in the rat subiculum

The subiculum is a structure that forms a bridge between the hippocampus and the entorhinal cortex (EC), and plays a major role in the memory consolidation process. Here, we demonstrate spike-timing-dependent plasticity (STDP) at the proximal excitatory inputs on the subicular pyramidal neurons of juvenile rat. Causal (positive) pairing of a single EPSP with a single back-propagating action potential (bAP) after a time interval of 10 ms (+10 ms) failed to induce plasticity. However, increasing the number of bAPs in a burst to three, at two different frequencies of 50 Hz (bAP burst) and 150 Hz, induced long-term depression (LTD) after a time interval of +10 ms in both the regular-firing (RF), and the weak burst firing (WBF) neurons. The LTD amplitude decreased with increasing time interval between the EPSP and the bAP burst. Reversing the order of the pairing of the EPSP and the bAP burst induced LTP at a time interval of -10 ms. This finding is in contrast with reports at other synapses, wherein prebefore postsynaptic (causal) pairing induced LTP and vice versa. Our results reaffirm the earlier observations that the relative timing of the pre- and postsynaptic activities can lead to multiple types of plasticity profiles. The induction of timing-dependent LTD (t-LTD) was dependent on postsynaptic calcium change via NMDA receptors in the WBF neurons, while it was independent of postsynaptic calcium change, but required active L-type calcium channels in the RF neurons. Thus the mechanism of synaptic plasticity may vary within a hippocampal subfield depending on the postsynaptic neuron involved. This study also reports a novel mechanism of LTD induction, where L-type calcium channels are involved in a presynaptically induced synaptic plasticity. The findings may have strong implications in the memory consolidation process owing to the central role of the subiculum and LTD in this process.

Conductivity Studies of Silver-, Potassium-, and Magnesium-Doped Hydroxyapatite

We report the electrical transport properties of silver-, potassium-, and magnesium-doped hydroxyapatites (HAs). While Ag+ or K+ doping to HA enhances the conductivity, Mg+2 doping lowers the conductivity when compared with undoped HA. The mechanism behind the observed differences in ionic conductivity has been discussed using the analysis of high-temperature frequency-dependent conductivity data, Cole-Cole plots of impedance data as well as on the basis of the frequency dependence of the imaginary part (M) of the complex electric modulus. The f(max) of modulus M decreased in silver- and potassium-doped samples in comparison with the undoped HA.

Analogous Synaptic Plasticity Profiles Emerge from Disparate Channel Combinations

An open question within the Bienenstock-Cooper-Munro theory for synaptic modification concerns the specific mechanism that is responsible for regulating the sliding modification threshold (SMT). In this conductance-based modeling study on hippocampal pyramidal neurons, we quantitatively assessed the impact of seven ion channels (R- and T-type calcium, fast sodium, delayed rectifier, A-type, and small-conductance calcium-activated (SK) potassium and HCN) and two receptors (AMPAR and NMDAR) on a calcium-dependent Bienenstock-Cooper-Munro-like plasticity rule. Our analysis with R- and T-type calcium channels revealed that differences in their activation-inactivation profiles resulted in differential impacts on how they altered the SMT. Further, we found that the impact of SK channels on the SMT critically depended on the voltage dependence and kinetics of the calcium sources with which they interacted. Next, we considered interactions among all the seven channels and the two receptors through global sensitivity analysis on 11 model parameters. We constructed 20,000 models through uniform randomization of these parameters and found 360 valid models based on experimental constraints on their plasticity profiles. Analyzing these 360 models, we found that similar plasticity profiles could emerge with several nonunique parametric combinations and that parameters exhibited weak pairwise correlations. Finally, we used seven sets of virtual knock-outs on these 360 models and found that the impact of different channels on the SMT was variable and differential. These results suggest that there are several nonunique routes to regulate the SMT, and call for a systematic analysis of the variability and state dependence of the mechanisms underlying metaplasticity during behavior and pathology.

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

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 hyperpolarization-activated 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.

Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain

Key points The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection. In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices. Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner. Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328. Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change. AbstractA rise in lactate concentration and the leak potassium channel TREK1 have been independently associated with cerebral ischaemia. Recent literature suggests lactate to be neuroprotective and TREK1 knockout mice show an increased sensitivity to brain and spinal cord ischaemia; however, the connecting link between the two is missing. Therefore we hypothesized that lactate might interact with TREK1 channels. In the present study, we show that lactate at ischaemic concentrations (15-30mm) at pH7.4 increases TREK1 current in CA1 stratum radiatum astrocytes and causes membrane hyperpolarization. We confirm the intracellular action of lactate on TREK1 in hippocampal slices using monocarboxylate transporter blockers and at single channel level in cell-free inside-out membrane patches. The intracellular effect of lactate on TREK1 is specific since other monocarboxylates such as pyruvate and acetate at pH7.4 failed to increase TREK1 current. Deletion and point mutation experiments suggest that lactate decreases the longer close dwell time incrementally with increase in lactate concentration by interacting with the histidine residue at position 328 (H328) in the carboxy terminal domain of the TREK1 channel. The interaction of lactate with H328 is dependent on the charge on the histidine residue since isosteric mutation of H328 to glutamine did not show an increase in TREK1 channel activity with lactate. This is the first demonstration of a direct effect of lactate on ion channel activity. The action of lactate on the TREK1 channel signifies a separate neuroprotective mechanism in ischaemia since it was found to be independent of the effect of acidic pH on channel activity. Key points The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection. In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices. Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner. Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328. Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change.