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 can be initiated at various subcellular compartments, such as axonal hillock, soma and dendrite. Mechanisms and physiological impacts for this relocation remain elusive, which may rely on input signal patterns and intrinsic properties in these subcellular compartments. We examined this hypothesis at the soma and axon of cortical pyramidal neurons by analyzing their spike capability and voltage-gated sodium channel dynamics in response to different input signals.
Electrophysiological recordings were simultaneously conducted at the somata and axons of identical pyramidal neurons in the cortical slices. The somata dominantly produced sequential spikes in response to long-time steady depolarization pulse, and the axons produced more spikes in response to fluctuated pulse. Compared with the axons, the somata possessed lower spike threshold and shorter refractory periods in response to long-time steady depolarization, and somatic voltage-gated sodium channels demonstrated less inactivation and easier reactivation in response to steady depolarization. Based on local VGSC dynamics, computational simulated spike initiation locations were consistent with those from the experiments. In terms of physiological impact, this input-dependent plasticity of spike initiation location made neuronal encoding to be efficient.
Long-time steady depolarization primarily induces somatic spikes and short-time pulses induce axonal spikes. The input signal patterns influence spike initiations at the axon or soma of cortical pyramidal neurons through modulating local voltage-gated sodium channel dynamics.
Action potential; Soma; Axon; Neuron and sodium channel
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
In cerebellar Purkinje cell dendrites, heterosynaptic calcium signaling induced by the proximal climbing fiber (CF) input controls plasticity at distal parallel fiber (PF) synapses. The substrate and regulation of this long-range dendritic calcium signaling are poorly understood. Using high-speed calcium imaging, we examine the role of active dendritic conductances. Under basal conditions, CF stimulation evokes T-type calcium signaling displaying sharp proximodistal decrement. Combined mGluR1 receptor activation and depolarization, two activity-dependent signals, unlock P/Q calcium spikes initiation and propagation, mediating efficient CF signaling at distal sites. These spikes are initiated in proximal smooth dendrites, independently from somatic sodium action potentials, and evoke high-frequency bursts of all-or-none fast-rising calcium transients in PF spines. Gradual calcium spike burst unlocking arises from increasing inactivation of mGluR1-modulated low-threshold A-type potassium channels located in distal dendrites. Evidence for graded activity-dependent CF calcium signaling at PF synapses refines current views on cerebellar supervised learning rules.
•The giant proximal CF input controls Ca2+ plasticity at distal PF-Purkinje synapses•We find mGluR1 activity and Purkinje cell depolarization to control CF calcium influx•Distal CF signaling is mediated by centrifugal dendritic calcium spikes bursts•Dendritic low-threshold A-type K+ channels modulation underlie calcium spike gating
Climbing fibers supervise cerebellar learning expressed as calcium-dependent plasticity at the parallel synapses on Purkinje cells. Otsu et al. find that activity-dependent parameters control heterosynaptic climbing fiber signaling by gating calcium spikes in Purkinje cell dendrites.
Rapid firing of cerebellar Purkinje neurons is facilitated in part by a voltage-gated Na+ (NaV) ‘resurgent’ current, which allows renewed Na+ influx during membrane repolarization. Resurgent current results from unbinding of a blocking particle that competes with normal channel inactivation. The underlying molecular components contributing to resurgent current have not been fully identified. In this study, we show that the NaV channel auxiliary subunit FGF14 ‘b’ isoform, a locus for inherited spinocerebellar ataxias, controls resurgent current and repetitive firing in Purkinje neurons. FGF14 knockdown biased NaV channels towards the inactivated state by decreasing channel availability, diminishing the ‘late’ NaV current, and accelerating channel inactivation rate, thereby reducing resurgent current and repetitive spiking. Critical for these effects was both the alternatively spliced FGF14b N-terminus and direct interaction between FGF14b and the NaV C-terminus. Together, these data suggest that the FGF14b N-terminus is a potent regulator of resurgent NaV current in cerebellar Purkinje neurons.
The cerebellum is a region of the brain that is involved in motor control, and it contains a special type of nerve cells called Purkinje neurons. Messages travel along neurons as electrical signals carried by sodium ions, which have a positive electric charge. Normally, when a neuron is ‘at rest’, the plasma membrane that surrounds the neuron prevents the sodium ions outside the cell from entering. To send an electrical signal, voltage-sensitive proteins in the membrane called sodium channels open up. This allows the sodium ions to enter the cell by passing through a pore in the channel protein, thereby changing the voltage across the membrane.
Once sodium channels open, they rapidly become ‘locked’ in a closed state, which allows the membrane voltage to return to its original value before another signal can be sent. This locked state also prevents sodium channels from reopening quickly. As a consequence most neurons cannot send successive electrical signals rapidly. Purkinje neurons are unusual because they can send many electrical signals in quick succession—known as rapid firing—without having to be reset each time.
Rapid firing is possible in Purkinje neurons because the channel proteins can be reopened to allow more Na+ to enter the cell, but it is not clear how this is controlled. Now, based on experiments on Purkinje neurons isolated from mice, Yan et al. have shown that a protein called FGF14 that binds to the sodium channel proteins can help them to reopen quickly in order to allow rapid firing.
Spinocerebellar ataxia is a degenerative disease caused by damage to the cerebellum that leads to loss of physical coordination. Some patients suffering from this disease carry mutations in the gene that makes the FGF14 protein. Therefore, understanding the role of FGF14 in the rapid firing of Purkinje neurons may aid the development of new treatments for this disease.
resurgent sodium current; cerebellum; spinocerebellar ataxia; cerebellar Purkinje neurons; electrophysiology; mouse
Gamma oscillations (∼30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency (‘fast-spiking') and synchronize the activity of numerous pyramidal cells by rhythmic inhibition (‘clockwork'). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited (‘interneuron energy hypothesis'). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.
brain slice; electrophysiology; energy metabolism; γ-aminobutyric acid; inhibitory interneuron; mitochondria
Voltage-gated sodium channels are responsible for the initiation and propagation of action potentials (APs). Two brain isoforms, Nav1.1 and Nav1.6, have very distinct cellular and subcellular expression. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment of fast-spiking GABAergic neurons, while Nav1.6 is found at the distal axon initial segment and nodes of Ranvier of both fast-spiking GABAergic and excitatory neurons. Interestingly, an auxiliary voltage-gated sodium channel subunit, Navβ4, is also enriched in the axon initial segment of fast-spiking GABAergic neurons. The C-terminal tail of Navβ4 is thought to mediate resurgent sodium current, an atypical current that occurs immediately following the action potential and is predicted to enhance excitability. To better understand the contribution of Nav1.1, Nav1.6 and Navβ4 to high frequency firing, we compared the properties of these two channel isoforms in the presence and absence of a peptide corresponding to part of the C-terminal tail of Navβ4. We used whole-cell patch clamp recordings to examine the biophysical properties of these two channel isoforms in HEK293T cells and found several differences between human Nav1.1 and Nav1.6 currents. Nav1.1 channels exhibited slower closed-state inactivation but faster open-state inactivation than Nav1.6 channels. We also observed a greater propensity of Nav1.6 to generate resurgent currents, most likely due to its slower kinetics of open-state inactivation, compared to Nav1.1. These two isoforms also showed differential responses to slow and fast AP waveforms, which were altered by the Navβ4 peptide. Although the Navβ4 peptide substantially increased the rate of recovery from apparent inactivation, Navβ4 peptide did not protect either channel isoform from undergoing use-dependent reduction with 10 Hz step-pulse stimulation or trains of slow or fast AP waveforms. Overall, these two channels have distinct biophysical properties that may differentially contribute to regulating neuronal excitability.
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
Asynchronous GABA release occurs at output synapses of fast-spiking interneurons in human and rat neocortex and is elevated in epileptic tissues from both species.
Down-regulation of GABAergic inhibition may result in the generation of epileptiform activities. Besides spike-triggered synchronous GABA release, changes in asynchronous release (AR) following high-frequency discharges may further regulate epileptiform activities. In brain slices obtained from surgically removed human neocortical tissues of patients with intractable epilepsy and brain tumor, we found that AR occurred at GABAergic output synapses of fast-spiking (FS) neurons and its strength depended on the type of connections, with FS autapses showing the strongest AR. In addition, we found that AR depended on residual Ca2+ at presynaptic terminals but was independent of postsynaptic firing. Furthermore, AR at FS autapses was markedly elevated in human epileptic tissue as compared to non-epileptic tissue. In a rat model of epilepsy, we found similar elevation of AR at both FS autapses and synapses onto excitatory neurons. Further experiments and analysis showed that AR elevation in epileptic tissue may result from an increase in action potential amplitude in the FS neurons and elevation of residual Ca2+ concentration. Together, these results revealed that GABAergic AR occurred at both human and rat neocortex, and its elevation in epileptic tissue may contribute to the regulation of epileptiform activities.
The balance between excitation and inhibition in the cerebral cortex is important for multiple brain functions. Down-regulation of GABA-induced inhibition disrupts this balance and may lead to epileptic seizures. Asynchronous release of GABA is known to occur at certain GABAergic synapses and represents release of inhibitory neurotransmitter that is not precisely timed to presynaptic action potentials. Whether asynchronous release is subject to change after the induction of epilepsy remains unclear. In this study, using simultaneous recordings from inhibitory fast-spiking neurons and excitatory pyramidal cells, we found that asynchronous release occurred at the output synapses of fast-spiking neurons in both human and rat neocortex. The occurrence of asynchronous release depended on the level of residual calcium at the presynaptic terminals but not on postsynaptic spiking. Further experiments using cortical tissue derived from human patients with intractable epilepsy and from a rat model of the disorder revealed an elevation of asynchronous release in epileptic cortex, possibly resulting from an increase in action potential amplitude of fast-spiking neurons and changes in calcium dynamics in their axon terminals. Taken together, these results demonstrate that asynchronous release is a fundamental property shared by neocortical fast-spiking neurons regardless of species, and the enhancement of asynchronous release in epileptic tissue suggests a role for it in regulating epileptic activities.
Long-term potentiation of inhibitory GABAergic transmission controls synaptic integration and action potential generation of specific neocortical neurons.
In the neocortex, the coexistence of temporally locked excitation and inhibition governs complex network activity underlying cognitive functions, and is believed to be altered in several brain diseases. Here we show that this equilibrium can be unlocked by increased activity of layer 5 pyramidal neurons of the mouse neocortex. Somatic depolarization or short bursts of action potentials of layer 5 pyramidal neurons induced a selective long-term potentiation of GABAergic synapses (LTPi) without affecting glutamatergic inputs. Remarkably, LTPi was selective for perisomatic inhibition from parvalbumin basket cells, leaving dendritic inhibition intact. It relied on retrograde signaling of nitric oxide, which persistently altered presynaptic GABA release and diffused to inhibitory synapses impinging on adjacent pyramidal neurons. LTPi reduced the time window of synaptic summation and increased the temporal precision of spike generation. Thus, increases in single cortical pyramidal neuron activity can induce an interneuron-selective GABAergic plasticity effectively altering the computation of temporally coded information.
The proper activity of cortical neurons (the brain cells responsible for memory and consciousness) relies on the precise integration of excitatory and inhibitory inputs. The excitation and inhibition (E/I) ratio has to remain constant both in time and strength to prevent neurological and psychiatric diseases. Fast inhibitory synaptic inputs to cortical pyramidal neurons originate from a rich diversity of GABAergic interneurons that operate a strict division of labor by differentially targeting precise regions of the pyramidal neurons. Here, we show that large pyramidal neurons of neocortical layer 5 can unlock the E/I ratio in response to their own activity. Excitatory activity of pyramidal neurons, in the form of membrane depolarization or trains of action potentials, induces a Ca2+-dependent mobilization of nitric oxide, which diffuses to inhibitory synapses and triggers a persistent enhancement of GABA release. Notably, this potentiation of inhibition is specific for synapses originating from parvalbumin (PV)-expressing interneurons that target mainly the perisomatic region of pyramidal neurons. Long-term potentiation of perisomatic inhibition, in turn, changes the ability of pyramidal neurons to integrate excitatory inputs as well as the temporal properties of their own action potential output. Selective plasticity of perisomatic inhibition can thus play a crucial role in cortical activity, such as sensory processing and integration.
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.
The six-layered mammalian neocortex evolved from the three-layered paleocortex, which is retained in present-day reptiles such as the turtle. Thus the turtle offers an opportunity to examine which cellular and circuit properties are fundamental to cortical function. We characterized the dendritic properties of pyramidal neurons in different cortical regions of mature turtles, Pseudemys scripta elegans, using whole cell recordings and calcium imaging from the axon, soma, and dendrites in a slice preparation. The firing properties, in response to intrasomatic depolarization, resembled those previously recorded with sharp electrodes in this preparation. Somatic spikes led to active backpropagating high-amplitude dendritic action potentials and intracellular calcium ion concentration ([Ca2+]i) changes at all dendritic locations, suggesting that both backpropagation and dendritic voltage-gated Ca2+ channels are primitive traits. We found no indication that Ca2+ spikes could be evoked in the dendrites, but fast Na+ spikes could be initiated there following intradendritic stimulation. Several lines of evidence indicate that fast, smaller-amplitude somatic spikes (“prepotentials”) that are easily recorded in this preparation are generated in the axon. Most synaptically activated [Ca2+]i changes resulted from Ca2+ entry through voltage-gated channels. In some cells synaptic stimulation evoked a delayed Ca2+ wave due to release from internal stores following activation of metabotropic glutamate receptors. With some small differences these properties resemble those of pyramidal neurons in mammalian species. We conclude that spike backpropagation, dendritic Ca2+ channels, and synaptically activated Ca2+ release are primitive and conserved features of cortical pyramidal cells, and therefore likely fundamental to cortical function.
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
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.
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
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
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.
Synaptic inputs from different brain areas are often targeted to distinct regions of neuronal dendritic arbors. Inputs to proximal dendrites usually produce large somatic EPSPs that efficiently trigger action potential (AP) output, whereas inputs to distal dendrites are greatly attenuated and may largely modulate AP output. In contrast to most other cortical and hippocampal neurons, hippocampal CA2 pyramidal neurons show unusually strong excitation by their distal dendritic inputs from entorhinal cortex (EC). In this study, we demonstrate that the ability of these EC inputs to drive CA2 AP output requires the firing of local dendritic Na+ spikes. Furthermore, we find that CA2 dendritic geometry contributes to the efficient coupling of dendritic Na+ spikes to AP output. These results provide a striking example of how dendritic spikes enable direct cortical inputs to overcome unfavorable distal synaptic locale to trigger axonal AP output and thereby enable efficient cortico-hippocampal information flow.
Cells called neurons carry information—in the form of electrical signals—around the brain. These cells connect to each other in complex networks and each neuron is able to form junctions, or synapses, with many neighbors. In a neuron, small electrical signals start from synapses at the tips of branched structures called dendrites. From there, these signals travel to the cell body of the neuron to activate a larger electrical signal—called an action potential—that travels along a long tail-like extension, called the axon, to reach synapses with other neurons.
In the dendrites, the small electrical signals can be amplified by rapid changes in the concentration of sodium ions, known as Na+ spikes. Although they were first recorded over 40 years ago, it is not clear how important the Na+ spikes are for triggering action potentials.
In this study, Sun et al. studied a type of neuron in the hippocampus called CA2 pyramidal neurons, which are involved in social memory and aggression. Unlike most other neurons in this region, CA2 neurons are strongly activated by signals from a neighboring region of the brain called the entorhinal cortex. The experiments show that Na+ spikes are able to travel from the dendrites to the cell body of these neurons, where they are required to trigger action potentials. However, this is not the case for other neurons in the hippocampus, where the Na+ spikes are very weak by the time they reach the cell body.
Sun et al. used a computational modeling technique to compare the different types of neurons in the hippocampus. The dendrites of these cells have different branching patterns and shapes, and the model suggests that this may explain the differences in how well the Na+ spikes travel to the cell body. The next major challenge is to understand the role of the Na+ spikes in social memory and other complex behaviors that are controlled by CA2 neurons.
dendritic excitability; action potential; dendritic spike; hippocampus; mouse
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.
The GABA projection neurons of the substantia nigra pars reticulata (SNr) are output neurons for the basal ganglia and thus critical for movement control. Their most striking neurophysiological feature is sustained, spontaneous high frequency spike firing. A fundamental question is: what are the key ion channels supporting the remarkable firing capability in these neurons? Recent studies indicate that these neurons express tonically active TRPC3 channels that conduct a Na-dependent inward current even at hyperpolarized membrane potentials. When the membrane potential reaches −60 mV, a voltage-gated persistent sodium current (INaP) starts to activate, further depolarizing the membrane potential. At or slightly below −50 mV, the large transient voltage-activated sodium current (INaT) starts to activate and eventually triggers the rapid rising phase of action potentials. SNr GABA neurons have a higher density of (INaT), contributing to the faster rise and larger amplitude of action potentials, compared with the slow-spiking dopamine neurons. INaT also recovers from inactivation more quickly in SNr GABA neurons than in nigral dopamine neurons. In SNr GABA neurons, the rising phase of the action potential triggers the activation of high-threshold, inactivation-resistant Kv3-like channels that can rapidly repolarize the membrane. These intrinsic ion channels provide SNr GABA neurons with the ability to fire spontaneous and sustained high frequency spikes. Additionally, robust GABA inputs from direct pathway medium spiny neurons in the striatum and GABA neurons in the globus pallidus may inhibit and silence SNr GABA neurons, whereas glutamate synaptic input from the subthalamic nucleus may induce burst firing in SNr GABA neurons. Thus, afferent GABA and glutamate synaptic inputs sculpt the tonic high frequency firing of SNr GABA neurons and the consequent inhibition of their targets into an integrated motor control signal that is further fine-tuned by neuromodulators including dopamine, serotonin, endocannabinoids, and H2O2.
action potential; basal ganglia; ion channel; Parkinson’s disease; substantia nigra; synapse
Neuron encodes and transmits information through generating sequences of output spikes, which is a high energy-consuming process. The spike is initiated when membrane depolarization reaches a threshold voltage. In many neurons, threshold is dynamic and depends on the rate of membrane depolarization (dV/dt) preceding a spike. Identifying the metabolic energy involved in neural coding and their relationship to threshold dynamic is critical to understanding neuronal function and evolution. Here, we use a modified Morris-Lecar model to investigate neuronal input-output property and energy efficiency associated with different spike threshold dynamics. We find that the neurons with dynamic threshold sensitive to dV/dt generate discontinuous frequency-current curve and type II phase response curve (PRC) through Hopf bifurcation, and weak noise could prohibit spiking when bifurcation just occurs. The threshold that is insensitive to dV/dt, instead, results in a continuous frequency-current curve, a type I PRC and a saddle-node on invariant circle bifurcation, and simultaneously weak noise cannot inhibit spiking. It is also shown that the bifurcation, frequency-current curve and PRC type associated with different threshold dynamics arise from the distinct subthreshold interactions of membrane currents. Further, we observe that the energy consumption of the neuron is related to its firing characteristics. The depolarization of spike threshold improves neuronal energy efficiency by reducing the overlap of Na+ and K+ currents during an action potential. The high energy efficiency is achieved at more depolarized spike threshold and high stimulus current. These results provide a fundamental biophysical connection that links spike threshold dynamics, input-output relation, energetics and spike initiation, which could contribute to uncover neural encoding mechanism.
spike threshold dynamic; input-output relation; energy efficiency; biophysical connection; spike initiation
Kv2 family “delayed-rectifier” potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60–80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from −70 mV, but not −80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at −70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation.
activation; deactivation; delayed-rectifier potassium channel; Guangxitoxin; Hodgkin-Huxley kinetics; Kv2
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.
Because of fast recovery from synaptic depression and fast-initiated action potentials, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in those of rodents.
Neuronal firing, synaptic transmission, and its plasticity form the building blocks for processing and storage of information in the brain. It is unknown whether adult human synapses are more efficient in transferring information between neurons than rodent synapses. To test this, we recorded from connected pairs of pyramidal neurons in acute brain slices of adult human and mouse temporal cortex and probed the dynamical properties of use-dependent plasticity. We found that human synaptic connections were purely depressing and that they recovered three to four times more swiftly from depression than synapses in rodent neocortex. Thereby, during realistic spike trains, the temporal resolution of synaptic information exchange in human synapses substantially surpasses that in mice. Using information theory, we calculate that information transfer between human pyramidal neurons exceeds that of mouse pyramidal neurons by four to nine times, well into the beta and gamma frequency range. In addition, we found that human principal cells tracked fine temporal features, conveyed in received synaptic inputs, at a wider bandwidth than for rodents. Action potential firing probability was reliably phase-locked to input transients up to 1,000 cycles/s because of a steep onset of action potentials in human pyramidal neurons during spike trains, unlike in rodent neurons. Our data show that, in contrast to the widely held views of limited information transfer in rodent depressing synapses, fast recovering synapses of human neurons can actually transfer substantial amounts of information during spike trains. In addition, human pyramidal neurons are equipped to encode high synaptic information content. Thus, adult human cortical microcircuits relay information at a wider bandwidth than rodent microcircuits.
Our ability to think, memorize information, and act appropriately depends on circuits of connected neurons in the brain. In these circuits, neurons pass information to each other using electric pulses (action potentials) that cause the release of chemical neurotransmitters, which alter the membrane electric potential of receiving neurons. Based on the inputs neurons receive, they decide whether to transmit action potentials to other neurons in the circuit to pass on information. During sequences of repeated information transfer, synaptic connections between two neurons temporarily become weaker by synaptic depression. Our knowledge of neuronal information transfer is based on rodent neurons. The properties of synaptic information transfer and synaptic depression in humans are not known. Here, we show that adult human neurons can transfer information with up to ten times higher rates than mouse neurons, because of a three to four times faster recovery from depression. Furthermore, we found that human neurons can respond faster to synaptic inputs, owing to faster initiation of action potentials. Human neurons can thereby reliably encode high input frequencies in their output. Thus, neuronal information transfer can have a substantially higher bandwidth in human neocortical circuits than in rodent brains.
Spike-timing-dependent plasticity (STDP) provides a cellular implementation of the Hebb postulate, which states that synapses, whose activity repeatedly drives action potential firing in target cells, are potentiated. At glutamatergic synapses onto hippocampal and neocortical pyramidal cells, synaptic activation followed by spike firing in the target cell causes long-term potentiation (LTP)—as predicted by Hebb—whereas excitatory postsynaptic potentials (EPSPs) evoked after a spike elicit long-term depression (LTD)—a phenomenon that was not specifically addressed by Hebb. In both instances the action potential in the postsynaptic target neuron is an instructive signal that is capable of supporting synaptic plasticity. STDP generally relies on the propagation of Na+ action potentials that are initiated in the axon hillhock back into the dendrite, where they cause depolarization and boost local calcium influx. However, recent studies in CA1 hippocampal pyramidal neurons have suggested that local calcium spikes might provide a more efficient trigger for LTP induction than backpropagating action potentials. Dendritic calcium spikes also play a role in an entirely different type of STDP that can be observed in cerebellar Purkinje cells. These neurons lack backpropagating Na+ spikes. Instead, plasticity at parallel fiber (PF) to Purkinje cell synapses depends on the relative timing of PF-EPSPs and activation of the glutamatergic climbing fiber (CF) input that causes dendritic calcium spikes. Thus, the instructive signal in this system is externalized. Importantly when EPSPs are elicited before CF activity, PF-LTD is induced rather than LTP. Thus, STDP in the cerebellum follows a timing rule that is opposite to its hippocampal/neocortical counterparts. Regardless, a common motif in plasticity is that LTD/LTP induction depends on the relative timing of synaptic activity and regenerative dendritic spikes which are driven by the instructive signal.
calcium; climbing fiber; dendrite; long-term depression; long-term potentiation; parallel fiber; Purkinje cell; pyramidal cell