Fundamentally, action potentials in the squid axon are consequence of the entrance of sodium ions during the depolarization of the rising phase of the spike mediated by the outflow of potassium ions during the hyperpolarization of the falling phase. Perfect metabolic efficiency with a minimum charge needed for the change in voltage during the action potential would confine sodium entry to the rising phase and potassium efflux to the falling phase. However, because sodium channels remain open to a significant extent during the falling phase, a certain overlap of inward and outward currents is observed. In this work we investigate the impact of ion overlap on the number of the adenosine triphosphate (ATP) molecules and energy cost required per action potential as a function of the temperature in a Hodgkin–Huxley model. Based on a recent approach to computing the energy cost of neuronal action potential generation not based on ion counting, we show that increased firing frequencies induced by higher temperatures imply more efficient use of sodium entry, and then a decrease in the metabolic energy cost required to restore the concentration gradients after an action potential. Also, we determine values of sodium conductance at which the hydrolysis efficiency presents a clear minimum.
Hodgkin–Huxley model; action potential; neuron metabolic energy; sodium entry; overlap load; regular-spiking cells
The ionic mechanism underlying optimal stimulus shapes that induce a neuron to fire an action potential, or spike, is relevant to understanding optimal information transmission and therapeutic stimulation in the nervous system. Here we analyze for the first time the ionic basis for stimulus optimality in the Hodgkin and Huxley model and for eliciting a spike in squid giant axons, the preparation for which the model was devised. The experimentally determined stimulus is a smoothly varying biphasic current waveform having a relatively long and shallow hyperpolarizing phase followed by a depolarizing phase of briefer duration. The hyperpolarizing phase removes a small degree of the resting level of Na+ channel inactivation. This result together with the subsequent depolarizing phase provides a signal that is energetically more efficient for eliciting spikes than rectangular current pulses. Sodium channel inactivation is the only variable that is changed during the stimulus waveform, other than the membrane potential, V. The activation variables for Na+ and K+ channels are unchanged throughout the stimulus. This result demonstrates how an optimal stimulus waveform relates to ionic dynamics and may have implications for energy efficiency of neural excitation in many systems including the mammalian brain.
The output of the neuronal digital spikes is fulfilled by axonal propagation and synaptic transmission to influence postsynaptic cells. Similar to synaptic transmission, spike propagation on the axon is not secure, especially in cerebellar Purkinje cells whose spiking rate is high. The characteristics, mechanisms and physiological impacts of propagation deceleration and infidelity remain elusive. The spike propagation is presumably initiated by local currents that raise membrane potential to the threshold of activating voltage-gated sodium channels (VGSC).
We have investigated the natures of spike propagation and the role of VGSCs in this process by recording spikes simultaneously on the somata and axonal terminals of Purkinje cells in cerebellar slices. The velocity and fidelity of spike propagation decreased during long-lasting spikes, to which the velocity change was more sensitive than fidelity change. These time-dependent deceleration and infidelity of spike propagation were improved by facilitating axonal VGSC reactivation, and worsen by intensifying VGSC inactivation.
Our studies indicate that the functional status of axonal VGSCs is essential to influencing the velocity and fidelity of spike propagation.
Axon; Neuron; Action potential; Spike propagation; Purkinje cell; Cerebellum
Neurons spike when their membrane potential exceeds a threshold value. In central neurons, the spike threshold is not constant but depends on the stimulation. Thus, input-output properties of neurons depend both on the effect of presynaptic spikes on the membrane potential and on the dynamics of the spike threshold. Among the possible mechanisms that may modulate the threshold, one strong candidate is Na channel inactivation, because it specifically impacts spike initiation without affecting the membrane potential. We collected voltage-clamp data from the literature and we found, based on a theoretical criterion, that the properties of Na inactivation could indeed cause substantial threshold variability by itself. By analyzing simple neuron models with fast Na inactivation (one channel subtype), we found that the spike threshold is correlated with the mean membrane potential and negatively correlated with the preceding depolarization slope, consistent with experiments. We then analyzed the impact of threshold dynamics on synaptic integration. The difference between the postsynaptic potential (PSP) and the dynamic threshold in response to a presynaptic spike defines an effective PSP. When the neuron is sufficiently depolarized, this effective PSP is briefer than the PSP. This mechanism regulates the temporal window of synaptic integration in an adaptive way. Finally, we discuss the role of other potential mechanisms. Distal spike initiation, channel noise and Na activation dynamics cannot account for the observed negative slope-threshold relationship, while adaptive conductances (e.g. K+) and Na inactivation can. We conclude that Na inactivation is a metabolically efficient mechanism to control the temporal resolution of synaptic integration.
Neurons spike when their combined inputs exceed a threshold value, but recent experimental findings have shown that this value also depends on the inputs. Thus, to understand how neurons respond to input spikes, it is important to know how inputs modify the spike threshold. Spikes are generated by sodium channels, which inactivate when the neuron is depolarized, raising the threshold for spike initiation. We found that inactivation properties of sodium channels could indeed cause substantial threshold variability in central neurons. We then analyzed in models the implications of this form of threshold modulation on neuronal function. We found that this mechanism makes neurons more sensitive to coincident spikes and provides them with an energetically efficient form of gain control.
Action potentials are the essential unit of neuronal encoding. Somatic sequential spikes in the central nervous system appear various in amplitudes. To be effective neuronal codes, these spikes should be propagated to axonal terminals where they activate the synapses and drive postsynaptic neurons. It remains unclear whether these effective neuronal codes are based on spike timing orders and/or amplitudes.
We investigated this fundamental issue by simultaneously recording the axon versus soma of identical neurons and presynaptic vs. postsynaptic neurons in the cortical slices. The axons enable somatic spikes in low amplitude be enlarged, which activate synaptic transmission in consistent patterns. This facilitation in the propagation of sequential spikes through the axons is mechanistically founded by the short refractory periods, large currents and high opening probability of axonal voltage-gated sodium channels.
An amplification of somatic incomplete spikes into axonal complete ones makes sequential spikes to activate consistent synaptic transmission. Therefore, neuronal encoding is likely based on spike timing order, instead of graded analogues.
An activity-dependent long-lasting asynchronous release of GABA from identified fast-spiking inhibitory neurons in the neocortex can impair the reliability and temporal precision of activity in a cortical network.
Networks of specific inhibitory interneurons regulate principal cell firing in several forms of neocortical activity. Fast-spiking (FS) interneurons are potently self-inhibited by GABAergic autaptic transmission, allowing them to precisely control their own firing dynamics and timing. Here we show that in FS interneurons, high-frequency trains of action potentials can generate a delayed and prolonged GABAergic self-inhibition due to sustained asynchronous release at FS-cell autapses. Asynchronous release of GABA is simultaneously recorded in connected pyramidal (P) neurons. Asynchronous and synchronous autaptic release show differential presynaptic Ca2+ sensitivity, suggesting that they rely on different Ca2+ sensors and/or involve distinct pools of vesicles. In addition, asynchronous release is modulated by the endogenous Ca2+ buffer parvalbumin. Functionally, asynchronous release decreases FS-cell spike reliability and reduces the ability of P neurons to integrate incoming stimuli into precise firing. Since each FS cell contacts many P neurons, asynchronous release from a single interneuron may desynchronize a large portion of the local network and disrupt cortical information processing.
In the cerebral cortex (neocortex) of the brain, fast-spiking (FS) inhibitory cells contact many principal pyramidal (P) neurons on their cell bodies, which allows the FS cells to control the generation of action potentials (neuronal output). FS-cell-mediated rhythmic and synchronous inhibition drives coherent network oscillations of large ensembles of P neurons, indicating that FS interneurons are needed for the precise timing of cortical circuits. Interestingly, FS cells are self-innervated by GABAergic autaptic contacts, whose synchronous activation regulates FS-cell precise firing. Here we report that high-frequency firing in FS interneurons results in a massive (>10-fold), delayed, and prolonged (for seconds) increase in inhibitory events, occurring at both autaptic (FS–FS) and synaptic (FS–P) sites. This increased inhibition is due to asynchronous release of GABA from presynaptic FS cells. Delayed and disorganized asynchronous inhibitory responses significantly affected the input–output properties of both FS and P neurons, suggesting that asynchronous release of GABA might promote network desynchronization. FS interneurons can fire at high frequency (>100 Hz) in vitro and in vivo, and are known for their reliable and precise signaling. Our results show an unprecedented action of these cells, by which their tight temporal control of cortical circuits can be broken when they are driven to fire above certain frequencies.
Postinhibitory rebound spiking is characteristic of several neuron types and brain regions, where it sustains spontaneous activity and central pattern generation. However, rebound spikes are rarely observed in the principal cells of the hippocampus under physiological conditions. We report that CA1 pyramidal neurons support rebound spikes mediated by hyperpolarization-activated inward current (Ih), and normally masked by A-type potassium channels (KA). In both experiments and computational models, KA blockage or reduction consistently resulted in a somatic action potential upon release from hyperpolarizing injections in the soma or main apical dendrite. Rebound spiking was systematically abolished by the additional blockage or reduction of Ih. Since the density of both KA and Ih increases in these cells with the distance from the soma, such “latent” mechanism may be most effective in the distal dendrites, which are targeted by a variety of GABAergic interneurons. Detailed computer simulations, validated against the experimental data, demonstrate that rebound spiking can result from activation of distal inhibitory synapses. In particular, partial KA reduction confined to one or few branches of the apical tuft may be sufficient to elicit a local spike following a train of synaptic inhibition. Moreover, the spatial extent and amount of KA reduction determines whether the dendritic spike propagates to the soma. These data suggest that the plastic regulation of KA can provide a dynamic switch to unmask postinhibitory spiking in CA1 pyramidal neurons. This newly discovered local modulation of postinhibitory spiking further increases the signal processing power of the CA1 synaptic microcircuitry.
In the developing hippocampus, GABA exerts depolarizing and excitatory actions and contributes to the generation of neuronal network driven giant depolarizing potentials (GDPs). Here, we studied spike time coding at immature GABAergic synapses and its impact on synchronization of the neuronal network during GDPs in the neonatal (postnatal days P2–6) rat hippocampal slices. Using extracellular recordings, we found that the delays of action potentials (APs) evoked by synaptic activation of GABA(A) receptors are long (mean, 65 ms) and variable (within a time window of 10–200 ms). During patch-clamp recordings, depolarizing GABAergic responses were mainly subthreshold and their amplification by persistent sodium conductance was required to trigger APs. AP delays at GABAergic synapses shortened and their variability reduced with an increase in intracellular chloride concentration during whole-cell recordings. Negative shift of the GABA reversal potential (EGABA) with low concentrations of bumetanide, or potentiation of GABA(A) receptors with diazepam reduced GDPs amplitude, desynchronized neuronal firing during GDPs and slowed down GDPs propagation. Partial blockade of GABA(A) receptors with bicuculline increased neuronal synchronization and accelerated GDPs propagation. We propose that spike timing at depolarizing GABA synapses is determined by intracellular chloride concentration. At physiological levels of intracellular chloride GABAergic depolarization does not reach the action potential threshold and amplification of GABAergic responses by non-inactivating sodium conductance is required for postsynaptic AP initiation. Slow and variable excitation at GABAergic synapse determines the level of neuronal synchrony and the rate of GDPs propagation in the developing hippocampus.
gamma aminobutyric acid; development; neonatal; hippocampus
Tetrodotoxin (TTX)-sensitive sodium channels carry large transient currents during action potentials and also “persistent” sodium current, a non-inactivating TTX-sensitive current present at subthreshold voltages. We examined gating of subthreshold sodium current in dissociated cerebellar Purkinje neurons and hippocampal CA1 neurons, studied at 37 °C with near-physiological ionic conditions. Unexpectedly, in both cell types small voltage steps at subthreshold voltages activated a substantial component of transient sodium current as well as persistent current. Subthreshold EPSP-like waveforms also activated a large component of transient sodium current, but IPSP-like waveforms engaged primarily persistent sodium current with only a small additional transient component. Activation of transient as well as persistent sodium current at subthreshold voltages produces amplification of EPSPs that is sensitive to the rate of depolarization and can help account for the dependence of spike threshold on depolarization rate, as previously observed in vivo.
CA1 pyramidal neuron; Purkinje neuron; persistent sodium current; IPSP; sodium channel
We studied the peripheral motor axons of the two pyloric dilator (PD) neurons of the stomatogastric ganglion in the lobster, Homarus americanus. Intracellular recordings from the motor nerve showed both fast and slow voltage- and activity-dependent dynamics. During rhythmic bursts, the PD axons displayed changes in spike amplitude and duration. Pharmacological experiments and the voltage-dependence of these phenomena suggest that inactivation of sodium and A-type potassium channels are responsible. In addition, the “resting” membrane potential was dependent on ongoing spike or burst activity, with more hyperpolarized values when activity was strong. Nerve stimulations, pharmacological block and current clamp experiments suggest that this is due to a functional antagonism between a slow after-hyperpolarization (sAHP) and inward rectification through hyperpolarization-activated current (IH). Dopamine application resulted in modest depolarization and “ectopic” peripheral spike initiation in the absence of centrally generated activity. This effect was blocked by CsCl and ZD7288, consistent with a role of IH. High frequency nerve stimulation inhibited peripheral spike initiation for several seconds, presumably due to the sAHP. Both during normal bursting activity and antidromic nerve stimulation, the conduction delay over the length of the peripheral nerve changed in a complex manner. This suggests that axonal membrane dynamics can have a substantial effect on the temporal fidelity of spike patterns propagated from a spike initiation site to a synaptic target, and that neuromodulators can influence the extent to which spike patterns are modified.
Central Pattern Generator; Neuromodulation; Crustacean; Neurohormones; Sag Potential; Spike Frequency Adaptation
The spatiotemporal control of neuronal excitability is fundamental to the inhibitory process. We now have a wealth of information about the active dendritic properties of cortical neurons including axonally generated sodium action potentials as well as local sodium spikelets generated in the dendrites, calcium plateau spikes, and NMDA spikes. All of these events have been shown to be highly modified by the spatiotemporal pattern of nearby inhibitory input which can drastically change the output firing mode of the neuron. This means that particular populations of interneurons embedded in the neocortical microcircuitry can more precisely control pyramidal cell output than has previously been thought. Furthermore, the output of any given neuron tends to feed back onto inhibitory circuits making the resultant network activity further dependent on inhibition. Network activity is therefore ultimately governed by the subcellular microcircuitry of the cortex and it is impossible to ignore the subcompartmentalization of inhibitory influence at the neuronal level in order to understand its effects at the network level. In this article, we summarize the inhibitory circuits that have been shown so far to act on specific dendritic compartments in vivo.
inhibition; interneuron; dendrite; cortex
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.
Dopamine is a neurotransmitter which plays important roles in the control of voluntary movement, motivation and reward, attention, and learning. Dysfunction of midbrain dopaminergic systems is involved in various diseases such as Parkinson's disease, schizophrenia and drug abuse. This underlines the importance of a tight regulation of dopamine levels in the brain. At the cellular level, the release of dopamine is directly correlated to the type of electrical activity (the firing pattern) of nerve cells that produce it, the so-called “dopaminergic neurons”. Therefore, an in depth understanding of the mechanisms underlying the electrical behavior of dopaminergic neurons is of critical importance to find new strategies for the treatment of diseases that result from dysfunction of this system.
Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.
Evidence suggests that maturation of inhibition is required for the development of plasticity to proceed in the visual cortex. However, the mechanisms by which increased inhibition promotes plasticity are not clear. Here we characterized the maturation of synaptic and intrinsic ionic properties of parvalbumin-positive interneurons, a prominent subtype of inhibitory neuron in the cortex. We used a simple integrate-and-fire model to simulate the influence of maturation of inhibition on associative plasticity rules. We simulated two input pathways that converged onto a single postsynaptic neuron. The temporal pattern of activity was constructed differently for the two pathways: one pathway represented visually-driven activity, while the other pathway represented sensory-deprived activity. In mature circuits it is established that postsynaptic cells can select for sensory-driven inputs over deprived inputs, even in the case that deprived inputs have an initial advantage in synaptic size or number. We demonstrated that maturation of inhibition was required for postsynaptic cells to appropriately select sensory-driven patterns of activity when challenged with an opponent pathway of greater size. These results outline a mechanism by which maturation of inhibition can promote plasticity in the young, a period of development that is characterized by heightened learning.
An unusual feature of the cerebellar cortex is that its output neurons, Purkinje cells, are GABAergic. Their high intrinsic firing rates1 (50 Hz) and extensive convergence2,3 predict that that target neurons in the cerebellar nuclei would be largely inhibited unless Purkinje cells pause their spiking, yet Purkinje and nuclear neuron firing rates do not always vary inversely4. A potential clue to how these synapses transmit information is that populations of Purkinje neurons synchronize their spikes during cerebellar behaviors5–11. If nuclear neurons respond to Purkinje synchrony, they may encode signals from subsets of inhibitory inputs7,12–14. Here we show in weanling and adult mice that nuclear neurons transmit the timing of synchronous Purkinje afferent spikes, owing to modest Purkinje-to-nuclear convergence ratios (~40:1), fast IPSC kinetics (τdecay=2.5 ms), and high intrinsic firing rates (~90 Hz). In vitro, dynamically clamped asynchronous IPSPs mimicking Purkinje afferents suppress nuclear cell spiking, whereas synchronous IPSPs entrain nuclear cell spiking. With partial synchrony, nuclear neurons time-lock their spikes to the synchronous subpopulation of inputs, even when only 2 of 40 afferents synchronize. In vivo, nuclear neurons reliably phase-lock to regular trains of molecular layer stimulation. Thus, cerebellar nuclear neurons can preferentially relay the spike timing of synchronized Purkinje cells to downstream premotor areas.
Purkinje neurons fire spontaneous action potentials at ~50 spikes/sec and generate more than 100 spikes/sec during cerebellum-mediated behaviors. Many voltage-gated channels, including Ca channels, can inactivate and/or facilitate with repeated stimulation, raising the question of how these channels respond to regular, rapid trains of depolarizations. To test whether Ca currents are modulated during firing, we recorded voltage-clamped Ca currents, predominantly carried by P-type Ca channels, from acutely dissociated mouse Purkinje neurons at 30–33°C (1 mM Ca). With 0.5 mM intracellular EGTA, 1-second trains of either spontaneous action potential waveforms or brief depolarizing steps at 50 Hz evoked Ca tail currents that were stable, remaining within 5% of the first tail current throughout the train. Higher frequency trains (100 and 200 Hz) elicited a maximal inactivation of <10%. To test whether this stability of Ca currents resulted from a lack of modulation or from an equilibrium between facilitation and inactivation, we manipulated the permeant ion (Ca vs. Ba) and Ca buffering (0.5 vs. 10 mM EGTA). With low buffering, Ba accelerated the initial inactivation evoked by 1-second trains, but reduced its extent at 200 hz, consistent with an early calcium-dependent facilitation (CDF) and late calcium-dependent inactivation (CDI) at high frequencies. Increasing the Ca buffer favored CDF. These data suggest that stable Ca current amplitudes result from a balance of CDF, CDI, and voltage-dependent inactivation. This modest net Ca-dependent modulation may contribute to the ability of Purkinje neurons to sustain long periods of regular firing and synaptic transmission.
P-type; CaV2.1; calcium channel; Ca dependent inactivation; spontaneous firing; cerebellum
Dynamic balance of excitation and inhibition is crucial for network stability and cortical processing, but it is unclear how this balance is achieved at different membrane potentials (Vm) of cortical neurons, as found during persistent activity or slow Vm oscillation. Here we report that a Vm-dependent modulation of recurrent inhibition between pyramidal cells (PCs) contributes to the excitation-inhibition balance. Whole-cell recording from paired layer-5 PCs in rat somatosensory cortical slices revealed that both the slow and the fast disynaptic IPSPs, presumably mediated by low-threshold spiking and fast spiking interneurons, respectively, were modulated by changes in presynaptic Vm. Somatic depolarization (>5 mV) of the presynaptic PC substantially increased the amplitude and shortened the onset latency of the slow disynaptic IPSPs in neighboring PCs, leading to a narrowed time window for EPSP integration. A similar increase in the amplitude of the fast disynaptic IPSPs in response to presynaptic depolarization was also observed. Further paired recording from PCs and interneurons revealed that PC depolarization increases EPSP amplitude and thus elevates interneuronal firing and inhibition of neighboring PCs, a reflection of the analog mode of excitatory synaptic transmission between PCs and interneurons. Together, these results revealed an immediate Vm-dependent modulation of cortical inhibition, a key strategy through which the cortex dynamically maintains the balance of excitation and inhibition at different states of cortical activity.
Proper functioning of the neocortex requires a balance between excitation and inhibition. This balance can be achieved through the operation of cortical microcircuits interweaved by excitatory and inhibitory neurons. Since the membrane potentials (Vm) of cortical neurons fluctuate at different levels during cortical activities, it is important to know how the balance of excitation and inhibition is dynamically maintained at different Vm. Recurrent inhibition between excitatory pyramidal cells is mediated by two distinct types of inhibitory interneurons. Here, we show that the amount of recurrent inhibition depends on the Vm levels of presynaptic pyramidal cells. Modest depolarization of a pyramidal cell substantially increases, and sometimes turns on, disynaptic inhibition on its neighboring pyramidal cells. We find that this effect is due to an increase in the strength of synaptic connections from the pyramidal cell to inhibitory interneurons and a consequent elevation of interneuronal firing. The depolarization-induced increase in synaptic strength from the pyramidal cell therefore reflects “analog-mode” signaling in cortical excitatory synapses. We thus reveal a profound impact of analog-mode signaling on the operation of cortical microcircuits and provide a new mechanism for dynamic control of the balance of cortical excitation and inhibition.
Voltage-dependent membrane conductances support specific neurophysiological properties. To investigate the mechanisms of coincidence detection, we activated gerbil medial superior olivary (MSO) neurons with dynamic current-clamp stimuli in vitro. Spike-triggered reverse-correlation analysis for injected current was used to evaluate the integration of subthreshold noisy signals. Consistent with previous reports, the partial blockade of low-threshold potassium channels (IKLT) reduced coincidence detection by slowing the rise of current needed on average to evoke a spike. However, two factors point toward the involvement of a second mechanism. First, the reverse correlation currents revealed that spike generation was associated with a preceding hyperpolarization. Second, rebound action potentials are 45% larger compared to depolarization-evoked spikes in the presence of an IKLT antagonist. These observations suggest that the sodium current (INa) was substantially inactivated at rest. To test this idea, INa was enhanced by increasing extracellular sodium concentration. This manipulation reduced coincidence detection, as reflected by slower spike-triggering current, and diminished the hyperpolarization phase in the reverse-correlation currents. As expected, a small outward bias current decreased the pre-spike hyperpolarization phase, and TTX blockade of INa nearly eliminated the hyperpolarization phase in the reverse correlation current. A computer model including Hodgkin-Huxley type conductances for spike generation and for IKLT showed reduction in coincidence detection when IKLT was reduced or when INa was increased. We hypothesize that desirable synaptic signals first remove some inactivation of INa and reduce activation of IKLT to create a brief temporal window for coincidence detection of subthreshold noisy signals.
Gamma frequency oscillations in cortical regions can be recorded during cognitive processes, including attention or memory tasks. These oscillations are generated locally as a result of reciprocal interactions between excitatory pyramidal cells and perisomatic inhibitory interneurons. Here, we examined the contribution of the three perisomatic interneuron types – the parvalbumin-containing fast-spiking basket (FSBC) and axo-axonic (AAC) cells, as well as the cholecystokinin-containing regular-spiking basket cells (RSBC) to cholinergically induced oscillations in hippocampal slices, a rhythmic activity that captures several features of the gamma oscillations recorded in vivo. By analyzing the spiking activities of single neurons recorded in parallel with local field potentials, we found that all three cell types fired phase-locked to the carbachol-induced oscillations, although with different frequencies and precision. During these oscillations FSBCs fired the most with the highest accuracy compared to the discharge of AACs and RSBCs. In further experiments we showed that activation of μ-opioid receptors by DAMGO, which significantly reduced the inhibitory, but not excitatory transmission, suppressed or even blocked network oscillations both in vitro and in vivo, leading to the desynchronization of pyramidal cell firing. Using paired recordings we demonstrated that carbachol application blocked GABA release from RSBCs and reduced it from FSBCs and AACs, whereas DAMGO further suppressed the GABA release only from FSBCs, but not from AACs.
These results collectively suggest that the rhythmic perisomatic inhibition, generating oscillatory fluctuation in local field potentials after carbachol treatment of hippocampal slices, is the result of periodic GABA release from FSBCs.
inhibition; rhythm; μ-opioid receptor; gamma oscillations; in vivo; in vitro
Purkinje neurons are the output cells of the cerebellar cortex and generate spikes in two distinct modes, known as simple and complex spikes. Revealing the point of origin of these action potentials, and how they conduct into local axon collaterals, is important for understanding local and distal neuronal processing and communication. By utilizing a recent improvement in voltage sensitive dye imaging technique that provided exceptional spatial and temporal resolution, we were able to resolve the region of spike initiation as well as follow spike propagation into axon collaterals for each action potential initiated on single trials. All fast action potentials, for both simple and complex spikes, whether occurring spontaneously or in response to a somatic current pulse or synaptic input, initiated in the axon initial segment. At discharge frequencies of less than approximately 250 Hz, spikes propagated faithfully through the axon and axon collaterals, in a saltatory manner. Propagation failures were only observed for very high frequencies or for the spikelets associated with complex spikes. These results demonstrate that the axon initial segment is a critical decision point in Purkinje cell processing and that the properties of axon branch points are adjusted to maintain faithful transmission.
axon; action potential; initiation; conduction failure; Purkinje
Transitions between different behavioral states, such as sleep or wakefulness, quiescence or attentiveness, occur in part through transitions from action potential bursting to single spiking. Cortical activity, for example, is determined in large part by the spike output mode from the thalamus, which is controlled by the gating of low-voltage–activated calcium channels. In the subiculum—the major output of the hippocampus—transitions occur from bursting in the delta-frequency band to single spiking in the theta-frequency band. We show here that these transitions are influenced strongly by the inactivation kinetics of voltage-gated sodium channels. Prolonged inactivation of sodium channels is responsible for an activity-dependent switch from bursting to single spiking, constituting a novel mechanism through which network dynamics are controlled by ion channel gating.
Prolonged inactivation of sodium channels represents a mechanism through which network dynamics may be controlled by ion channel gating properties.
We combined in vitro intracellular recording from prefrontal cortical neurons with simulated synaptic activity of a layer 5 prefrontal microcircuit using a dynamic clamp. During simulated in vivo background conditions, the cell responded to a brief depolarization with a sequence of spikes that outlasted the depolarization, mimicking the activity of a cell recorded during the delay period of a working memory task in the behaving monkey. The onset of sustained activity depended on the number of action potentials elicited by the cue-like depolarization. Too few spikes failed to provide enough NMDA drive to elicit sustained reverberations; too many spikes activated a slow intrinsic hyperpolarization current that prevented spiking; an intermediate number of spikes produced sustained activity. When high dopamine levels were simulated by depolarizing the cell and by increasing the amount of NMDA current, the cell exhibited spontaneous ‘up-states’ that terminated by the activation of a slow intrinsic hyperpolarizing current. The firing rate during the delay period could be effectively modulated by the standard deviation of the inhibitory background synaptic noise without significant changes in the background firing rate before cue onset. These results suggest that the balance between fast feedback inhibition and slower AMPA and NMDA feedback excitation is critical in initiating persistent activity and that the maintenance of persistent activity may be regulated by the amount of correlated background inhibition.
Neurogliaform cells in the rat elicit combined GABAA and GABAB receptor-mediated postsynaptic responses on cortical pyramidal cells and establish electrical synapses with various interneuron types. However, the involvement of GABAB receptors in postsynaptic effects of neurogliaform cells on other GABAergic interneurons is not clear. We measured the postsynaptic effects of neurogliaform cells in vitro applying simultaneous whole-cell recordings in human and rat cortex. Single action potentials of human neurogliaform cells evoked unitary IPSPs composed of GABAA and GABAB receptor-mediated components in various types of inteneuron and in pyramidal cells. Slow IPSPs were combined with homologous and heterologous electrical coupling between neurogliaform cells and several human interneuron types. In the rat, single action potentials in neurogliaform cells elicited GABAB receptor-mediated component in responses of neurogliaform, regular spiking, and fast spiking interneurons following the GABAA receptor-mediated component in postsynaptic responses. In conclusion, human and rat neurogliaform cells elicit slow IPSPs and reach GABAA and GABAB receptors on several interneuron types with a connection-specific involvement of GABAB receptors. The electrical synapses recorded between human neurogliaform cells and various interneuron types represent the first electrical synapses recorded in the human cortex.
neurogliaform; cortex; GABAA receptor; GABAB receptor; human
Small-conductance Ca2+-activated K+ channels (SK channels) modulate excitability and curtail excitatory postsynaptic potentials (EPSPs) in neuronal dendrites. Here, we demonstrate long-lasting plasticity of intrinsic excitability (IE) in dendrites that results from changes in the gain of this regulatory mechanism. Using dendritic patch-clamp recordings from rat cerebellar Purkinje cells, we find that somatic depolarization or parallel fiber (PF) burst stimulation induce long-term amplification of synaptic responses to climbing fiber (CF) or PF stimulation, and enhance the amplitude of passively propagated sodium spikes. Dendritic plasticity is mimicked and occluded by the SK channel blocker apamin, and is absent in Purkinje cells from SK2 null mice. Triple-patch recordings from two dendritic sites and the soma, and confocal calcium imaging studies show that local stimulation limits dendritic plasticity to the activated compartment of the dendrite. This plasticity mechanism allows Purkinje cells to adjust the SK2-mediated control of dendritic excitability in an activity-dependent manner.
Adaptation is commonly defined as a decrease in response to a constant stimulus. In the auditory system such adaptation is seen at multiple levels. However, the first-order central neurons of the interaural time difference (ITD) detection circuit encode information in the timing of spikes rather than the overall firing rate. We investigated adaptation during in vitro whole-cell recordings from chick nucleus magnocellularis (NM) neurons. Injection of noisy, depolarizing current caused an increase in firing rate and a decrease in spike time precision that developed over approximately 20 seconds. This adaptation depends on sustained depolarization, is independent of firing, and is eliminated by α-Dendrotoxin (0.1 μM) implicating slow inactivation of low-threshold voltage-activated K+ channels as its mechanism. This process may alter both firing rate and spike timing precision of phase-locked inputs to coincidence detector neurons in nucleus laminaris and thereby adjust the precision of sound localization.
sound localization; nucleus magnocellularis; potassium channel; phase-locking; spike-timing precision; coincidence detection
Excitatory pyramidal neurons and inhibitory interneurons constitute the main elements of cortical circuitry and have distinctive morphologic and electrophysiological properties. Here, we differentiate them by analyzing the time course of their action potentials (APs) and characterizing their receptive field properties in auditory cortex. Pyramidal neurons have longer APs and discharge as Regular-Spiking Units (RSUs), while basket and chandelier cells, which are inhibitory interneurons, have shorter APs and are Fast-Spiking Units (FSUs). To compare these neuronal classes we stimulated cat primary auditory cortex neurons with a dynamic moving ripple stimulus and constructed single-unit spectrotemporal receptive fields (STRFs) and their associated nonlinearities. FSUs had shorter latencies, broader spectral tuning, greater stimulus specificity, and higher temporal precision than RSUs. The STRF structure of FSUs was more separable, suggesting more independence between spectral and temporal processing regimes. The nonlinearities associated with the two cell classes was indicative of higher feature selectivity for FSUs. These global functional differences between RSUs and FSUs suggest fundamental distinctions between putative excitatory and inhibitory neurons that shape auditory cortical processing.