Slow Potential Oscillations Research Articles

How Modeling Can Reconcile Apparently Discrepant Experimental Results: The Case of Pacemaking in Dopaminergic Neurons

Midbrain dopaminergic neurons are endowed with endogenous slow pacemaking properties. In recent years, many different groups have studied the basis for this phenomenon, often with conflicting conclusions. In particular, the role of a slowly-inactivating L-type calcium channel in the depolarizing phase between spikes is controversial, and the analysis of slow oscillatory potential (SOP) recordings during the blockade of sodium channels has led to conflicting conclusions. Based on a minimal model of a dopaminergic neuron, our analysis suggests that the same experimental protocol may lead to drastically different observations in almost identical neurons. For example, complete L-type calcium channel blockade eliminates spontaneous firing or has almost no effect in two neurons differing by less than 1% in their maximal sodium conductance. The same prediction can be reproduced in a state of the art detailed model of a dopaminergic neuron. Some of these predictions are confirmed experimentally using single-cell recordings in brain slices. Our minimal model exhibits SOPs when sodium channels are blocked, these SOPs being uncorrelated with the spiking activity, as has been shown experimentally. We also show that block of a specific conductance (in this case, the SK conductance) can have a different effect on these two oscillatory behaviors (pacemaking and SOPs), despite the fact that they have the same initiating mechanism. These results highlight the fact that computational approaches, besides their well known confirmatory and predictive interests in neurophysiology, may also be useful to resolve apparent discrepancies between experimental results.

What makes DA neurons tick? Role of Ca2+ sources and inward currents in setting the regular pacemaking of dopaminergic neurons

Dopamine (DA) neurons show regular, pacemaking fir-ing in the range 1-8 Hz inin vitro preparations. Thecurrents involved in this pacemaking behavior are notfully understood. The slow oscillatory potential (SOP),evident after the application of TTX, is known todepend on the mutual interaction between L-type Ca2+and small conductance (SK) K+ currents. The SOPoscillates in a frequency range similar to the pacemakingfiring rate and it is assumed to be responsible for deter-mining this pacemaking frequency [1]. However, recentresults indicate that the SOP’sfrequencyisnotcorre-lated with spontaneous pacemaking frequency [2,3].Furthermore there is experimental evidence indicatingthat pacemaking does not require the influx of Ca2+through L-type Ca2+ channels [4,5]. Figure 1A illus-trates this last point from a modeling approach. Theblack trace corresponds to the spontaneous firing of themodel DA neuron and in blue the SOP. After simulatedblock of L-type current no activity is observed (green)but this is recovered (red) by injecting a virtual L-typecurrent into the soma (cf. [5]). Figure 1B on the otherhand illustrates the possible role of the fast Na+ currentin reestablishing pacemaking. Black and blue traces aresimilar to those in panel A; however pacemaking is rees-tablished by shifting the Na+ activation curve in ahyperpolarization direction (green). We explore the role

Regulation of firing frequency in a computational model of a midbrain dopaminergic neuron

Dopaminergic (DA) neurons of the mammalian midbrain exhibit unusually low firing frequencies in vitro. Furthermore, injection of depolarizing current induces depolarization block before high frequencies are achieved. The maximum steady and transient rates are about 10 and 20 Hz, respectively, despite the ability of these neurons to generate bursts at higher frequencies in vivo. We use a three-compartment model calibrated to reproduce DA neuron responses to several pharmacological manipulations to uncover mechanisms of frequency limitation. The model exhibits a slow oscillatory potential (SOP) dependent on the interplay between the L-type Ca(2+) current and the small conductance K(+) (SK) current that is unmasked by fast Na(+) current block. Contrary to previous theoretical work, the SOP does not pace the steady spiking frequency in our model. The main currents that determine the spontaneous firing frequency are the subthreshold L-type Ca(2+) and the A-type K(+) currents. The model identifies the channel densities for the fast Na(+) and the delayed rectifier K(+) currents as critical parameters limiting the maximal steady frequency evoked by a depolarizing pulse. We hypothesize that the low maximal steady frequencies result from a low safety factor for action potential generation. In the model, the rate of Ca(2+) accumulation in the distal dendrites controls the transient initial frequency in response to a depolarizing pulse. Similar results are obtained when the same model parameters are used in a multi-compartmental model with a realistic reconstructed morphology, indicating that the salient contributions of the dendritic architecture have been captured by the simpler model.

Cav1.3 Channel Voltage Dependence, Not Ca2+Selectivity, Drives Pacemaker Activity and Amplifies Bursts in Nigral Dopamine Neurons

Ca(v)1.3 (alpha 1D) L-type Ca(2+) channels have been implicated in substantia nigra (SN) dopamine (DA) neuron pacemaking and vulnerability to Parkinson's disease. These effects may arise from the depolarizing current and cytoplasmic Ca(2+) elevation produced by Ca(v)1.3 channels at subthreshold membrane potentials. However, the assumption that the Ca(2+) selectivity of Ca(v)1.3 channels is essential has not been tested. In this study the properties of SN DA neuron L-type Ca(2+) channels responsible for driving pacemaker activity in juvenile rat brain slices were probed by replacing native channels blocked with the dihydropyridine nimodipine with virtual channels generated by dynamic clamp. Surprisingly, virtual L-type channels that mimic native and recombinant Ca(v)1.3 channels supported pacemaker activity even though dynamic clamp currents are not carried by Ca(2+). This effect is specific because pacemaker activity could not be restored by tonic current injection, virtual nonselective leak channels or virtual NMDA receptors, which share with L-type channels a negative slope conductance region in their current-voltage (I-V) curve. Altering virtual channels showed that the production of pacemaker activity depended on the characteristic voltage dependence of DA neuron L-type channels, while activation kinetics and reversal potential were not critical parameters. Virtual L-type channels also supported slow oscillatory potentials and enhanced firing rate during evoked bursts. Thus, Ca(v)1.3 channel voltage dependence, rather than Ca(2+) selectivity, drives pacemaker activity and amplifies bursts in SN DA neurons.

Electrogenic calcium pump contributes to dopamine neuron repolarization

Dopaminergic neurons (DA) in vitro can produce two distinct firing patterns: single spikes, which are called slow oscillatory potentials (SOP), and square underlying bursting activity. Previously [1], we proposed a conductancebased computational model that explained the mechanisms of both SOP and square wave activity. Based on experimental data, the SOP mechanism was driven by a calcium (Ca) L-type current and an apamin-sensitive small conductance (SK) current. The square waves could be generated by partially blocking the SK current, but to repolarize the cell, a slow potassium current was hypothesized. Experiments on DA suggested that an ether-a-gogo potassium current could play the role of the hypothetical slow potassium current. Experiments also showed that Ca is a major player in both SOP and square wave firing. Calcium removal is an elusive mechanism and we previously considered that Ca pump is nonelectrogenic [1,2]. However, a nonelectrogenic Ca pump leads to equal rates of Ca influx and efflux at steady state and also equal rates of charge influx and efflux. As a result, once Ca concentration equilibrates, there should be no persistent inward calcium current, which contradicts experimental observations. In this paper, we hypothesize that Ca pump contributes to cell repolarization. Experimental results already published and our numerical simulations based on electrogenic Ca pump support this hypothesis.

A simplified model of dopaminergic neuron

A minimal model of a dopamine cell in vitro in the pres-ence of tetrodoxin (TTX) and tetraethyl ammonium (TEA)was developed to simulate two types of subthresholdoscillations: the slow oscillatory potential (SOP – see Fig-ure 1A) and the square wave (Figure 1B) that can be pro-duced by the abolition of the SOP by apamin. The L-typecalcium current drives both types of oscillation. The smallconductance potassium channel repolarizes the SOP, andwe propose that the ether-a-go-go related potassium chan-nel repolarizes the square wave. We further suggest thatthe role of this current in vivo is to relieve depolarizationblock. The model predicts that blocking the ether-a-go-gocurrent will elongate the plateau of the square wave andblocking the hyperpolarization-activated potassium cur-rent shortens the period of oscillations. In addition, themodel predicts that blocking the ether-a-go-go currentwill speed up the SOP. The model also predicts that cal-cium chelation converts SOPs into square waves by block-ing the increase in the small conductance (SK) current.Multiple-parameter bifurcation diagrams were used toinvestigate the properties of the firing patterns generatedby our model (Figure 2).

Boosting slow oscillations during sleep potentiates memory

There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.

Technique for eliminating nonessential components in the refinement of a model of dopamine neurons

A technique for model reduction is applied to a mathematical model of the midbrain dopamine neuron. The relevance of calcium-mediated inactivation of L- and N-type currents in a mathematical model of the midbrain dopamine neuron was tested for two firing patterns exhibited by these cells in vitro. We found that calcium-mediated inactivation of L- and N-type currents could be removed without causing significant changes in both the slow oscillatory potential (SOP) and the apamin-induced square-wave patterns.

The Neurophysiological Validation of the Hyperpolarization Theory of Internal Inhibition

The experiments in conscious non-immobilized rabbits showed that cessation of the reactions without reinforcement (elaboration of the internal inhibition) is accompanied by an enhanced phasic state, by alternation of activation and inhibition of neuron firing, and by the corresponding slow potential oscillation (SPO). These changes can be either localized, predominantly in the structures of conditioned stimulus, or, under enhancement of the inhibitory state, generalized in the brain structures. On the basis of our experience and published data, it is concluded that the above event results from relative enhancement of the inhibitory hyperpolarizing processes due to increase in reactivity of the inhibitory systems to stimulus, which acquires inhibitory properties during learning. Changes in the excitability and reactivity of neuron populations appearing during enhancement of the hyperpolarizing inhibition, and differing in the various brain structures, play an active role in the execution of the main function of the internal inhibition: limitation of excitation transmission to the effectors. An inhibitory mediator gamma aminobutyric acid (GABA) is of great importance in inhibiting the excitation in response to the stimulus which lost its biological significance. These experimental data and their interpretation in the light of published data give the basis for the development of the hyperpolarization theory of internal inhibition.

Very slow potential oscillations in locus coeruleus and dorsal raphe nucleus under different illumination in freely moving rats

Recent findings have revealed very slow (<0.5 Hz) oscillatory phenomena in the structures of the brain visual system. It has been proposed that very slow brain potentials in an extremely slow domain, less than 0.1 Hz, recorded from the lateral geniculate complex and primary visual cortex are associated with periodic influences originating from the locus coeruleus and dorsal raphe nucleus. The present study was performed to test the hypothesis that extremely slow brain potential oscillatory patterns in the locus coeruleus and dorsal raphe nucleus during several types of visual stimulation – light exposure, darkness, and photostimulation – are similar to those in the primary visual cortex and lateral geniculate complex under the same conditions of illumination. The results support this hypothesis. Specifically, spectral patterns of multisecond oscillations in the range of 0.02–0.04 Hz and fluctuations in the domain of minutes (below 0.002 Hz) were present in both the locus coeruleus and dorsal raphe nucleus and were similar to those found in the primary visual cortex and lateral geniculate complex. Additionally, we detected significant increases in the power spectra of multisecond oscillations in both nuclei in response to photostimulation ( P <0.05). Our tentative conclusion is that extremely slow potentials in the locus coeruleus and dorsal raphe nucleus contribute to the regulation of extremely slow activity in the brain visual system.

Very slow potential oscillations in locus coeruleus and dorsal raphe nucleus under different illumination in freely moving rats

Recent findings have revealed very slow (<0.5 Hz) oscillatory phenomena in the structures of the brain visual system. It has been proposed that very slow brain potentials in an extremely slow domain, less than 0.1 Hz, recorded from the lateral geniculate complex and primary visual cortex are associated with periodic influences originating from the locus coeruleus and dorsal raphe nucleus. The present study was performed to test the hypothesis that extremely slow brain potential oscillatory patterns in the locus coeruleus and dorsal raphe nucleus during several types of visual stimulation – light exposure, darkness, and photostimulation – are similar to those in the primary visual cortex and lateral geniculate complex under the same conditions of illumination. The results support this hypothesis. Specifically, spectral patterns of multisecond oscillations in the range of 0.02–0.04 Hz and fluctuations in the domain of minutes (below 0.002 Hz) were present in both the locus coeruleus and dorsal raphe nucleus and were similar to those found in the primary visual cortex and lateral geniculate complex. Additionally, we detected significant increases in the power spectra of multisecond oscillations in both nuclei in response to photostimulation ( P<0.05). Our tentative conclusion is that extremely slow potentials in the locus coeruleus and dorsal raphe nucleus contribute to the regulation of extremely slow activity in the brain visual system.

D-tubocurarine reduces GABA responses in rat substantia nigra dopamine neurons.

SynapseVolume 47, Issue 3 p. 236-239 D-Tubocurarine reduces GABA responses in rat substantia nigra dopamine neurons Luigi Caputi, Luigi Caputi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorC. Peter Bengtson, C. Peter Bengtson IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorEzia Guatteo, Ezia Guatteo IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorGiorgio Bernardi, Giorgio Bernardi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorNicola B. Mercuri, Corresponding Author Nicola B. Mercuri [email protected] IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalyFondazione IRCCS S. Lucia, Experimental Neurology Lab, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this author Luigi Caputi, Luigi Caputi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorC. Peter Bengtson, C. Peter Bengtson IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorEzia Guatteo, Ezia Guatteo IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this authorGiorgio Bernardi, Giorgio Bernardi IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalySearch for more papers by this authorNicola B. Mercuri, Corresponding Author Nicola B. Mercuri [email protected] IRCCS – Fondazione Santa Lucia, Via Ardeatina 306, 00179, Rome, Italy Clinica Neurologica Università di Roma – Tor Vergata, Rome, ItalyFondazione IRCCS S. Lucia, Experimental Neurology Lab, Via Ardeatina 306, 00179, Rome, ItalySearch for more papers by this author First published: 09 December 2002 https://doi.org/10.1002/syn.10164Citations: 5AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume47, Issue31 March 2003Pages 236-239 RelatedInformation

Cardiac pacemaker mechanisms in the ostracod crustacean Vargula hilgendorfii

The heart of the ostracod crustacean Vargula hilgendorfii has a single intrinsic neuron that morphologically appears to innervate the myocardium. We, therefore, examined the heart activity electrophysiologically to determine whether the heartbeat is neurogenic. Each heartbeat is associated with a myocardial action potential composed of a spike potential followed by a plateau potential. The frequency of the action potential is not stable but changes successively over a wide range. The action potential is not preceded by a pacemaker potential and has an inflection in its rising phase. The myocardial cells couple electrically and fire almost simultaneously. The frequency of the action potential was unchanged by injection of depolarizing or hyperpolarizing current into the myocardium. However, slow oscillatory potentials appeared during the depolarization and its frequency was higher with increasing current intensity. Application of 1-μM tetrodotoxin (TTX) depolarized the myocardial membrane and completely prevented the action potential. During this depolarization, slow oscillatory potentials often appeared spontaneously. These results suggest that, although the myocardium has a property of conditional oscillator, the heartbeat is driven by the single cell cardiac ganglion that has both pacemaker and motor functions.

Calcium dynamics underlying pacemaker-like and burst firing oscillations in midbrain dopaminergic neurons: a computational study.

A mathematical model of midbrain dopamine neurons has been developed to understand the mechanisms underlying two types of calcium-dependent firing patterns that these cells exhibit in vitro. The first is the regular, pacemaker-like firing exhibited in a slice preparation, and the second is a burst firing pattern sometimes exhibited in the presence of apamin. Because both types of oscillations are blocked by nifedipine, we have focused on the slow calcium dynamics underlying these firing modes. The underlying oscillations in membrane potential are best observed when action potentials are blocked by the application of TTX. This converts the regular single-spike firing mode to a slow oscillatory potential (SOP) and apamin-induced bursting to a slow square-wave oscillation. We hypothesize that the SOP results from the interplay between the L-type calcium current (I(Ca,L)) and the apamin-sensitive calcium-activated potassium current (I(K,Ca,SK)). We further hypothesize that the square-wave oscillation results from the alternating voltage activation and calcium inactivation of I(Ca,L). Our model consists of two components: a Hodgkin-Huxley-type membrane model and a fluid compartment model. A material balance on Ca(2+) is provided in the cytosolic fluid compartment, whereas calcium concentration is considered constant in the extracellular compartment. Model parameters were determined using both voltage-clamp and calcium-imaging data from the literature. In addition to modeling the SOP and square-wave oscillations in dopaminergic neurons, the model provides reasonable mimicry of the experimentally observed response of SOPs to TEA application and elongation of the plateau duration of the square-wave oscillations in response to calcium chelation.

TFast Network Oscillations in the Hippocampal CA1 Region of the Behaving Rat

This study examined intermittent, high-frequency (100-200 Hz) oscillatory patterns in the CA1 region of the hippocampus in the absence of theta activity, i.e., during and in between sharp wave (SPW) bursts. Pyramidal and interneuronal activity was phase-locked not only to large amplitude (>7 SD from baseline) oscillatory events, which are present mainly during SPWs, but to smaller amplitude (<4 SD) patterns, as well. Large-amplitude events were in the 140-200 Hz, "ripple" frequency range. Lower-amplitude events, however, contained slower, 100-130 Hz ("slow") oscillatory patterns. Fast ripple waves reversed just below the CA1 pyramidal layer, whereas slow oscillatory potentials reversed in the stratum radiatum and/or in the stratum oriens. Parallel CA1-CA3 recordings revealed correlated CA3 field and unit activity to the slow CA1 waves but not to fast ripple waves. These findings suggest that fast ripples emerge in the CA1 region, whereas slow (100-130 Hz) oscillatory patterns are generated in the CA3 region and transferred to the CA1 field.

Electrophysiological characterization of dopaminergic and non-dopaminergic neurones in organotypic slice cultures of the rat ventral mesencephalon

The aim of the present study was to characterize electrophysiologically neurones in organotypic cultures of the rat ventral mesencephalon and to compare these results with results published for the same neurones in other types of preparation. Intracellular recordings were obtained in 3- to 8-week-old organotypic slice cultures of the ventral mesencephalon prepared from new-born rats. Dopaminergic neurones were distinguished from non-dopaminergic neurones by staining with the autofluorescent serotonin analogue 5,7-dihydroxytryptamine and briefly viewing the preparation with short exposures to ultraviolet (UV) light (365 nm). Short exposures to UV light did not affect the electrophysiological properties. There were no significant differences between dopaminergic and non-dopaminergic neurones with regard to resting membrane potential or action potential threshold and amplitude, and in both types of neurone spontaneous burst activity and glutamatergic excitatory postsynaptic potentials were seen. There were differences in the following parameters, which can be used to distinguish between the two types of neurone. Dopaminergic neurones had broad action potentials (2-9 ms), high input resistance (mean 81 M omega), were silent or fired spontaneously at a low frequency (0-9 Hz), and no spontaneous GABAA-ergic inhibitory postsynaptic potentials or inward rectification were present. In contrast, non-dopaminergic neurones had fast action potentials (0.6-3.2 ms), low input resistance (mean 32 M omega), were silent or fired spontaneously at relatively high firing frequency (0-28 Hz), and sometimes inhibitory postsynaptic potentials and inward rectification were seen. In the presence of 1 microM tetrodotoxin and 10 mM tetraethylammonium, Ca2+ spikes could be evoked in both dopaminergic and non-dopaminergic neurones. Dopaminergic neurones in 3- to 8-week-old organotypic slice cultures have a number of distinguishing electrophysiological characteristics similar to those recorded in other types of acute or cultured preparations. However, some intrinsic regulatory mechanisms, namely the slow oscillatory potentials, inward rectification and the K+ current, IA, seem to be missing in the cultured neurones.

Role of excitatory amino acid and GABA B receptors in the generation of epileptiform activity in disinhibited hippocampal slice cultures

Selective excitatory amino acid- and GABA B-receptor antagonists were used to examine the role these receptors play in epileptiform burst discharge elicited by blocking GABA A receptor-mediated inhibition in hippocampal slice cultures of the rat. Application of bicuculline caused a single ictal burst followed by interjetai bursting. The N-methyl- d-aspartate receptor antagonist, d-2-amino-5-phosphonovalerate, reduced the depolarizing envelope underlying interictal discharge, and accentuated the appearance of concomitant slow oscillatory potentials, which occurred synchronously in all CA3 cells. The non- N-methyl- d-aspartate receptor antagonists, 6-nitro-7sulphamoyl-benzo(F)quinoxaline and 6-cyano-7-nitro-quinoxaline-2 3-dione, blocked interictal bursting at high concentrations, and low concentrations of 6-cyano-7-nitro-quinoxaline-2,3-dione selectively eliminated the slow oscillations in an all-or-none manner, leaving the depolarizing envelope. No effects of either metabotropic glutamate receptor antagonists or of dihydropyridine Ca 2+ channel agonists or antagonists on evoked interictal discharge were observed. 6-Cyano-7-nitro-quinoxaline-2,3-dione-resistant interictal-like discharge could be obtained in the presence of bicuculline when the external Mg 2+ concentration was reduced from 0.5–1.5 mM. The GABA B receptor antagonist CGP 35348 prolonged individual evoked interictal bursts, and caused the appearance of spontaneous ictal-like discharges. The implications of these results are discussed with regard to the mechanisms of epileptogenesis and to potential therapeutic intervention.

Nifedipine- and omega-conotoxin-sensitive Ca2+ conductances in guinea-pig substantia nigra pars compacta neurones.

1. The membrane properties of substantia nigra pars compacta (SNc) neurones were recorded in guinea-pig in vitro brain slices. 2. In the presence of tetrodotoxin (TTX) a Ca(2+)-dependent slow oscillatory potential (SOP) was generated. Application of 0.5-20 microM nifedipine abolished both spontaneous and evoked SOPs. A tetraethylammonium chloride (TEA)-promoted high-threshold Ca2+ spike (HTS) was little affected by nifedipine. On the other hand, omega-conotoxin applied either locally or via the perfusion medium (1-10 microM) blocked a part of the HTS, but it did not alter the SOP. 3. In normal medium nifedipine blocked the spontaneous discharge, decreased the interspike interval (ISI) recorded during depolarizing current injections and selectively reduced the slow component of the spike after-hyperpolarization (AHP). omega-Conotoxin decreased both the rising and falling slopes of the normal action potential, reduced the peak amplitude of the spike AHP, and, in some of the neurones, reduced the ISI during depolarization. The Na+ spikes recorded in Ca(2+)-free medium were not altered by omega-conotoxin. 4. The SOP was not blocked by octanol (100-200 microM), amiloride (100-250 microM), or Ni2+ (100-300 microM). However, at 500 microM Ni2+ attenuated the SOP. 5. Application of apamin (0.5-2.0 microM) induced irregular firing or bursting, abolished the slow component of the spike AHP and reduced its peak amplitude. In the presence of TTX and apamin long-duration plateau potentials occurred, which were subsequently blocked by nifedipine. 6. In Ca(2+)-free, Co(2+)-containing medium TTX-sensitive spikes and voltage plateaux were generated by depolarizing current pulses. It is suggested that a persistent Na+ conductance underlies the plateaux, which may be co-activated during the SOP. 7. The results suggest that the Ca2+ currents underlying the SOP and the HTS are different and that they activate at least two Ca(2+)-dependent K+ conductances. These conductances play major roles in the maintenance of spontaneous discharge and in control of membrane excitability.

Internodal potassium currents can generate ectopic impulses in mammalian myelinated axons

Positive clinical symptoms can arise from ectopic action potentials in several disorders of myelinated axons. Here we report that an elevated K+ concentration in the periaxonal, internodal space can cause internodal K+ currents to become excitatory, resulting in slow potential oscillations and associated bursts of ectopic spikes. Ectopic firing may therefore be favoured by conditions in which periaxonal K+ buffering is compromised.

Sub-populations of pars compacta neurons in the substantia nigra: The significance of qualitatively and quantitatively distinct conductances

In the substantia nigra pars compacta neurons can be classified in two sub-populations. In this study the distinguishing criteria have been the presence of four distinct calcium-dependent potentials, two each generated selectively and exclusively in each cell type. One class of cells, found in the more caudal pars compacta, displays calcium-mediated, slow oscillatory potentials which occur spontaneously and generate long-duration afterhyperpolarizations. A second, much faster calcium spike can be evoked after the blockade of sodium and potassium channels. This spike has a high generation threshold and is followed by a fast afterhyperpolarization. The other group of neurons is distributed principally in the rostral substantia nigra, at the level of the mammilary bodies. In these cells, a low-threshold calcium spike is generated that (i) inactivates at depolarized potentials (ii) has no active negative phase, and (iii) causes burst firing action potentials. In all these three respects, this transient differs from the slow oscillatory potential in the more caudal group of neurons. In addition, a short-duration calcium-dependent potential can be evoked at a high threshold. Both the low- and high-threshold spikes of the rostral cells are attenuated in experiments where dendrites have been sectioned prior to the recording. The membrane properties of the caudal cell group, including the fast calcium spike, are unaffected by dendritic sectioning. It is suggested that in the guinea-pig the calcium conductances in the caudal neurons operate in or near the cell body and might play a large (though not necessarily exclusive) role in regulating autorhythmicity. In the more rostral cells, the characteristics of their particular calcium conductances which seem to be located more distally would prompt a mediating function in the secretion, and subsequent action, of neuroactive substances from dendrites.