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

2015 ◽  
Vol 113 (1) ◽  
pp. 23-43 ◽  
Author(s):  
Poonam Mishra ◽  
Rishikesh Narayanan
Keyword(s):  
Dominant Role ◽  
Input Resistance ◽  
Resting Membrane Potential ◽  
Voltage Response ◽  
Hcn Channels ◽  
Type K ◽  
Conductance States ◽  
The Impact ◽  
High Conductance

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.

Differential Impact of Miniature Synaptic Potentials on the Soma and Dendrites of Pyramidal Neurons In Vivo

1997 ◽  
Vol 78 (3) ◽  
pp. 1735-1739 ◽  
Author(s):  
Denis Paré ◽  
Elen Lebel ◽  
Eric J. Lang
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Input Resistance ◽  
Differential Impact ◽  
Synaptic Potentials ◽  
Ampa Antagonists ◽  
Intact Brain ◽  
The Impact

Paré, Denis, Elen LeBel, and Eric J. Lang. Differential impact of miniature synaptic potentials on the somata and dendrites of pyramidal neurons in vivo. J. Neurophysiol. 78: 1735–1739, 1997. We studied the impact of transmitter release resistant to tetrodotoxin (TTX) in morphologically identified neocortical pyramidal neurons recorded intracellularly in barbiturate-anesthetized cats. It was observed that TTX-resistant release occurs in pyramidal neurons in vivo and at much higher frequencies than was previously reported in vitro. Further, in agreement with previous findings indicating that GABAergic and glutamatergic synapses are differentially distributed in the somata and dendrites of pyramidal cells, we found that most miniature synaptic potentials were sensitive to γ-aminobutyric acid-A (GABAA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists in presumed somatic and dendritic impalements, respectively. Pharmacological blockage of spontaneous synaptic events produced large increases in input resistance that were more important in dendritic (≈50%) than somatic (≈10%) impalements. These findings imply that in the intact brain, pyramidal neurons are submitted to an intense spike-independent synaptic bombardment that decreases the space constant of the cells. These results should be taken into account when extrapolating in vitro findings to intact brains.

scholarly journals Adaptive Exponential Integrate-and-Fire Model as an Effective Description of Neuronal Activity

2005 ◽  
Vol 94 (5) ◽  
pp. 3637-3642 ◽  
Author(s):  
Romain Brette ◽  
Wulfram Gerstner
Keyword(s):  
Simple Model ◽  
Expressive Power ◽  
Detailed Model ◽  
Fire Model ◽  
Integrate And Fire ◽  
Conductance States ◽  
Effective Description ◽  
High Conductance

We introduce a two-dimensional integrate-and-fire model that combines an exponential spike mechanism with an adaptation equation, based on recent theoretical findings. We describe a systematic method to estimate its parameters with simple electrophysiological protocols (current-clamp injection of pulses and ramps) and apply it to a detailed conductance-based model of a regular spiking neuron. Our simple model predicts correctly the timing of 96% of the spikes (±2 ms) of the detailed model in response to injection of noisy synaptic conductances. The model is especially reliable in high-conductance states, typical of cortical activity in vivo, in which intrinsic conductances were found to have a reduced role in shaping spike trains. These results are promising because this simple model has enough expressive power to reproduce qualitatively several electrophysiological classes described in vitro.

scholarly journals Thalamocortical synapses in the cat visual system in vivo are weak and unreliable

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Madineh Sedigh-Sarvestani ◽  
Larry A Palmer ◽  
Diego Contreras
Keyword(s):  
Visual System ◽  
Dynamic Properties ◽  
Short Term Plasticity ◽  
V1 Neurons ◽  
Membrane Fluctuations ◽  
Conductance States ◽  
Constrained Models ◽  
High Conductance

The thalamocortical synapse of the visual system has been central to our understanding of sensory computations in the cortex. Although we have a fair understanding of the functional properties of the pre and post-synaptic populations, little is known about their synaptic properties, particularly in vivo. We used simultaneous recordings in LGN and V1 in cat in vivo to characterize the dynamic properties of thalamocortical synaptic transmission in monosynaptically connected LGN-V1 neurons. We found that thalamocortical synapses in vivo are unreliable, highly variable and exhibit short-term plasticity. Using biologically constrained models, we found that variable and unreliable synapses serve to increase cortical firing by means of increasing membrane fluctuations, similar to high conductance states. Thus, synaptic variability and unreliability, rather than acting as system noise, do serve a computational function. Our characterization of LGN-V1 synaptic properties constrains existing mathematical models, and mechanistic hypotheses, of a fundamental circuit in computational neuroscience.

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

2012 ◽  
Vol 107 (8) ◽  
pp. 2083-2095 ◽  
Author(s):  
Sean H. White ◽  
C. Devin Brisson ◽  
R. David Andrew
Keyword(s):  
Pyramidal Neurons ◽  
Cortical Excitability ◽  
Neuronal Damage ◽  
Input Resistance ◽  
Stroke Onset ◽  
Light Transmittance ◽  
Resting Membrane Potential ◽  
Whole Cell ◽  
Anoxic Depolarization

As an immediate consequence of stroke onset, failure of the Na+-K+-ATPase pump evokes a propagating anoxic depolarization (AD) across gray matter. Acute neuronal swelling and dendritic beading arise within seconds in the future ischemic core, imaged as changes in light transmittance (ΔLT). AD is itself not a target for drug-based reduction of stroke injury because it is generated in the 1st min of stroke onset. Peri-infarct depolarizations (PIDs) are milder AD-like events that recur during the hours following AD and contribute to infarct expansion. Inhibiting PIDs with drugs could limit expansion. Two types of drugs, “caines” and σ1-receptor ligands, have been found to inhibit AD onset (and may also oppose PID initiation), yet their underlying actions have not been examined. Imaging ΔLT in the CA1 region simultaneously with whole cell current-clamp recording from CA1 pyramidal neurons reveal that the elevated LT front and onset of the AD are coincident. Either dibucaine or carbetapentane pretreatment significantly delays AD onset without affecting resting membrane potential or neuronal input resistance. Dibucaine decreases excitability by raising spike threshold and decreasing action potential (AP) frequency, whereas carbetapentane eliminates the fast afterhyperpolarization while accentuating the slow afterhyperpolarization to reduce AP frequency. Orthodromic and antidromic APs are eliminated by dibucaine within 15 min but not by carbetapentane. Thus both drugs reduce cortical excitability at the level of the single pyramidal neuron but through strikingly different mechanisms. In vivo, both drugs would likely inhibit recurring PIDs in the expanding penumbra and so potentially could reduce developing neuronal damage over many hours poststroke when PIDs occur.

Extracellular Potassium and Seizures: Excitation, Inhibition and the Role of Ih

2016 ◽  
Vol 26 (08) ◽  
pp. 1650044 ◽  
Author(s):  
Lihua Wang ◽  
Suzie Dufour ◽  
Taufik A. Valiante ◽  
Peter L. Carlen
Keyword(s):  
Neuronal Excitability ◽  
Seizure Activity ◽  
Membrane Properties ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Hcn Channels ◽  
Extracellular Potassium Concentration ◽  
Prolonged Seizure

Seizure activity leads to increases in extracellular potassium concentration ([K[Formula: see text]]o), which can result in changes in neuronal passive and active membrane properties as well as in population activities. In this study, we examined how extracellular potassium modulates seizure activities using an acute 4-AP induced seizure model in the neocortex, both in vivo and in vitro. Moderately elevated [K[Formula: see text]]o up to 9[Formula: see text]mM prolonged seizure durations and shortened interictal intervals as well as depolarized the neuronal resting membrane potential (RMP). However, when [K[Formula: see text]]o reached higher than 9[Formula: see text]mM, seizure like events (SLEs) were blocked and neurons went into a depolarization-blocked state. Spreading depression was never observed as the blockade of ictal events could be reversed within 1–2[Formula: see text]min after the raised [K[Formula: see text]]o was changed back to control levels. This concentration-dependent dual effect of [K[Formula: see text]]o was observed using in vivo and in vitro mouse brain preparations as well as in human neocortical tissue resected during epilepsy surgery. Blocking the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, modulated the elevated [K[Formula: see text]]o influence on SLEs by promoting the high [K[Formula: see text]]o inhibitory actions. These results demonstrate biphasic actions of raised [K[Formula: see text]]o on neuronal excitability and seizure activity.

Biophysical Characterization of Rat Caudal Hypothalamic Neurons: Calcium Channel Contribution to Excitability

2000 ◽  
Vol 84 (6) ◽  
pp. 2896-2903 ◽  
Author(s):  
Yi-Ping Fan ◽  
Eric M. Horn ◽  
Tony G. Waldrop
Keyword(s):  
Membrane Potential ◽  
Low Voltage ◽  
Input Resistance ◽  
Calcium Currents ◽  
Resting Membrane Potential ◽  
Calcium Dependent ◽  
Rhythmic Firing ◽  
Almost All

Neurons in the caudal hypothalamus (CH) are responsible for the modulation of various processes including respiratory and cardiovascular output. Previous results from this and other laboratories have demonstrated in vivo that these neurons have firing rhythms matched to the respiratory and cardiovascular cycles. The goal of the present study was to characterize the biophysical properties of neurons in the CH with particular emphasis in those properties responsible for rhythmic firing behavior. Whole cell, patch-clamped CH neurons displayed a resting membrane potential of −58.0 ± 1.1 mV and an input resistance of 319.3 ± 16.6 MΩ when recorded in current-clamp mode in an in vitro brain slice preparation. A large proportion of these neurons displayed postinhibitory rebound (PIR) that was dependent on the duration and magnitude of hyperpolarizing current as well as the resting membrane potential of the cell. Furthermore these neurons discharged tonically in response to a depolarizing current pulse at a depolarized resting membrane potential (more positive than −65 mV) but switched to a rapid burst of firing to the same stimulus when the resting membrane potential was lowered. The PIR observed in these neurons was calcium dependent as demonstrated by the ability to block its amplitude by perfusion of Ca2+-free bath solution or by application of Ni2+ (0.3–0.5 mM) or nifedipine (10 μM). These properties suggest that low-voltage-activated (LVA) calcium current is involved in the PIR and bursting firing of these CH neurons. In addition, high-voltage-activated calcium responses were detected after blockade of outward potassium current or in Ba2+-replacement solution. In addition, almost all of the CH neurons studied showed spike frequency adaptation that was decreased following Ca2+ removal, indicating the involvement of Ca2+-dependent K+ current ( I K,Ca) in these cells. In conclusion, CH neurons have at least two different types of calcium currents that contribute to their excitability; the dominant current is the LVA or T-type. This LVA current appears to play a significant role in the bursting characteristics that may underlie the rhythmic firing of CH neurons.

scholarly journals Hyperexcitability of Sensory Neurons in Fragile X Mouse Model

2021 ◽  
Vol 14 ◽  
Author(s):  
Pan-Yue Deng ◽  
Oshri Avraham ◽  
Valeria Cavalli ◽  
Vitaly A. Klyachko
Keyword(s):  
Mouse Model ◽  
Sensory Neuron ◽  
Sensory Neurons ◽  
Fragile X ◽  
Input Resistance ◽  
Resting Membrane Potential ◽  
Hcn Channels ◽  
Satellite Glial Cells ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in Fmr1 KO mice, manifested by markedly increased action potential (AP) firing rate and decreased threshold. Unlike excitability changes found in many central neurons, no significant changes were observed in AP rising and falling time, peak potential, amplitude, or duration. Sensory neuron hyperexcitability was caused primarily by increased input resistance, without changes in cell capacitance or resting membrane potential. Analyses of the underlying mechanisms revealed reduced activity of HCN channels and reduced expression of HCN1 and HCN4 in Fmr1 KO compared to WT. A selective HCN channel blocker abolished differences in all measures of sensory neuron excitability between WT and Fmr1 KO neurons. These results reveal a hyperexcitable state of peripheral sensory neurons in Fmr1 KO mice caused by dysfunction of HCN channels. In addition to the intrinsic neuronal dysfunction, the accompanying paper examines deficits in sensory neuron association/communication with their enveloping satellite glial cells, suggesting contributions from both neuronal intrinsic and extrinsic mechanisms to sensory dysfunction in the FXS mouse model.

Hyperpolarization-Activated Cation Channels: From Genes to Function

2009 ◽  
Vol 89 (3) ◽  
pp. 847-885 ◽  
Author(s):  
Martin Biel ◽  
Christian Wahl-Schott ◽  
Stylianos Michalakis ◽  
Xiangang Zong
Keyword(s):  
Nervous System ◽  
Drug Targets ◽  
Cardiac Pacemaker ◽  
Rhythmic Activity ◽  
Convincing Evidence ◽  
Cation Channels ◽  
Resting Membrane Potential ◽  
Hcn Channels ◽  
Hcn Channel ◽  
The Impact

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises four members (HCN1-4) that are expressed in heart and nervous system. The current produced by HCN channels has been known as Ih (or If or Iq). Ih has also been designated as pacemaker current, because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons. Extensive studies over the last decade have provided convincing evidence that Ih is also involved in a number of basic physiological processes that are not directly associated with rhythmicity. Examples for these non-pacemaking functions of Ih are the determination of the resting membrane potential, dendritic integration, synaptic transmission, and learning. In this review we summarize recent insights into the structure, function, and cellular regulation of HCN channels. We also discuss in detail the different aspects of HCN channel physiology in the heart and nervous system. To this end, evidence on the role of individual HCN channel types arising from the analysis of HCN knockout mouse models is discussed. Finally, we provide an overview of the impact of HCN channels on the pathogenesis of several diseases and discuss recent attempts to establish HCN channels as drug targets.

Bursting and oscillating neurons of the cat basolateral amygdaloid complex in vivo: electrophysiological properties and morphological features

1995 ◽  
Vol 74 (3) ◽  
pp. 1179-1191 ◽  
Author(s):  
D. Pare ◽  
H. C. Pape ◽  
J. Dong
Keyword(s):  
Inward Rectification ◽  
Resting Membrane Potential ◽  
Voltage Response ◽  
Projection Neurons ◽  
Morphological Identification ◽  
Current Pulses ◽  
Bursting Neurons ◽  
Early Peak ◽  
Spike Bursts

1. To characterize the physiological properties of lateral and basolateral (BL) amygdaloid neurons, intracellular recordings were performed in barbiturate-anesthetized cats. Morphological identification of recorded cells was achieved by intracellular injection of neurobiotin. Two types of physiologically identified projection neurons were distinguished in the BL and lateral nuclei. 2. The first type of neurons prevailed in the BL nucleus (80% of BL cells). Their resting membrane potential (Vm) averaged -66 +/- 4.9 (SE) mV. They generated stereotyped spike doublets or bursts in response to threshold depolarizing pulses. In most cells, depolarizing pulses of higher amplitude elicited spike bursts or doublets at a shorter latency followed by a nonadapting train of single spikes whose frequency rose with the amplitude of the current pulses. However, 15% of BL bursting neurons generated repetitive spike bursts or doublets in response to prolonged depolarizing current pulses. The response of BL bursting neurons to hyperpolarizing current pulses revealed the presence of slow inward rectification in the form of a depolarizing sag, thus suggesting the presence of a hyperpolarization-activated current. 3. The second type of neurons prevailed in the lateral nucleus. Their resting Vm was quite polarized (-74 +/- 2.85 mV) and they generated slow Vm oscillations (2-10 Hz) upon steady depolarization beyond congruent to -62 mV. The frequency of the oscillation increased with the amount of depolarizing current. In the majority of cells, analysis of voltage responses to subthreshold current pulses revealed the presence of voltage- and time-dependent rectification in the depolarizing direction. Current pulses that brought the Vm to -65 mV and beyond elicited a voltage response that reached an early peak and then decayed. Increasing the amplitude of the pulse decreased the latency of the early peak until it triggered an action potential. Current-voltage plots demonstrated inward rectification in the depolarizing direction. At the break of hyperpolarizing current pulses applied at depolarized levels, the Vm overshot prepulse values and generated one or more oscillatory cycles. 4. An important proportion of bursting and oscillating neurons (45.8% and 29%, respectively) were physiologically identified as projection neurons by antidromic invasion from the basal forebrain, entorhinal cortex, or perirhinal cortex. The conduction velocity of bursting and oscillating neurons estimated from the latency of antidromic spikes was low (< or = 2.5 m/s). 5. Most bursting and oscillating neurons of the BL nucleus were spiny cells with a pyramidal morphology. Four to eight dendritic trunks emerged from the apex, base, and sides of their triangular soma.(ABSTRACT TRUNCATED AT 400 WORDS)

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