Gap junctions desynchronize a neural circuit to stabilize insect flight.

Insect asynchronous flight is one of the most prevalent forms of animal locomotion used by more than 600,000 species. Despite profound insights into the motor patterns1, biomechanics2,3 and aerodynamics underlying asynchronous flight4,5, the architecture and function of the central-pattern-generating (CPG) neural network remain unclear. Here, on the basis of an experiment-theory approach including electrophysiology, optophysiology, Drosophila genetics and mathematical modelling, we identify a miniaturized circuit solution with unexpected properties. The CPG network consists of motoneurons interconnected by electrical synapses that, in contrast to doctrine, produce network activity splayed out in time instead of synchronized across neurons. Experimental and mathematical evidence support a generic mechanism for network desynchronization that relies on weak electrical synapses and specific excitability dynamics of the coupled neurons. In small networks, electrical synapses can synchronize or desynchronize network activity, depending on the neuron-intrinsic dynamics and ion channel composition. In the asynchronous flight CPG, this mechanism translates unpatterned premotor input into stereotyped neuronal firing with fixed sequences of cell activation that ensure stable wingbeat power and, as we show, is conserved across multiple species. Our findings prove a wider functional versatility of electrical synapses in the dynamic control of neural circuits and highlight the relevance of detecting electrical synapses in connectomics.

How neuronal morphology impacts the synchronisation state of neuronal networks.

The biophysical properties of neurons not only affect how information is processed within cells, they can also impact the dynamical states of the network. Specifically, the cellular dynamics of action-potential generation have shown relevance for setting the (de)synchronisation state of the network. The dynamics of tonically spiking neurons typically fall into one of three qualitatively distinct types that arise from distinct mathematical bifurcations of voltage dynamics at the onset of spiking. Accordingly, changes in ion channel composition or even external factors, like temperature, have been demonstrated to switch network behaviour via changes in the spike onset bifurcation and hence its associated dynamical type. A thus far less addressed modulator of neuronal dynamics is cellular morphology. Based on simplified and anatomically realistic mathematical neuron models, we show here that the extent of dendritic arborisation has an influence on the neuronal dynamical spiking type and therefore on the (de)synchronisation state of the network. Specifically, larger dendritic trees prime neuronal dynamics for in-phase-synchronised or splayed-out activity in weakly coupled networks, in contrast to cells with otherwise identical properties yet smaller dendrites. Our biophysical insights hold for generic multicompartmental classes of spiking neuron models (from ball-and-stick-type to anatomically reconstructed models) and establish a connection between neuronal morphology and the susceptibility of neural tissue to synchronisation in health and disease.

A feedforward inhibitory premotor circuit for auditory-vocal interactions in zebra finches.

During vocal exchanges, hearing specific auditory signals can provoke vocal responses or suppress vocalizations to avoid interference. These abilities result in the widespread phenomenon of vocal turn taking, yet little is known about the neural circuitry that regulates the input-dependent timing of vocal replies. Previous work in vocally interacting zebra finches has highlighted the importance of premotor inhibition for precisely timed vocal output. By developing physiologically constrained mathematical models, we derived circuit mechanisms based on feedforward inhibition that enable both the temporal modulation of vocal premotor drive as well as auditory suppression of vocalization during listening. Extracellular recordings in HVC during the listening phase confirmed the presence of auditory-evoked response patterns in putative inhibitory interneurons, along with corresponding signatures of auditory-evoked activity suppression. Further, intracellular recordings of identified neurons projecting to HVC from the upstream sensorimotor nucleus, nucleus interfacialis (NIf), shed light on the timing of auditory inputs to this network. The analysis of incrementally time-lagged interactions between auditory and premotor activity in the model resulted in the prediction of a window of auditory suppression, which could be, in turn, verified in behavioral data. A phasic feedforward inhibition model consistently explained the experimental results. This mechanism highlights a parsimonious and generalizable principle for how different driving inputs (vocal and auditory related) can be integrated in a single sensorimotor circuit to regulate two opposing vocal behavioral outcomes: the controlled timing of vocal output or the suppression of overlapping vocalizations.

Activity-mediated accumulation of potassium induces a switch in firing pattern and neuronal excitability type.

During normal neuronal activity, ionic concentration gradients across a neuron's membrane are often assumed to be stable. Prolonged spiking activity, however, can reduce transmembrane gradients and affect voltage dynamics. Based on mathematical modeling, we investigated the impact of neuronal activity on ionic concentrations and, consequently, the dynamics of action potential generation. We find that intense spiking activity on the order of a second suffices to induce changes in ionic reversal potentials and to consistently induce a switch from a regular to an intermittent firing mode. This transition is caused by a qualitative alteration in the system's voltage dynamics, mathematically corresponding to a co-dimension-two bifurcation from a saddle-node on invariant cycle (SNIC) to a homoclinic orbit bifurcation (HOM). Our electrophysiological recordings in mouse cortical pyramidal neurons confirm the changes in action potential dynamics predicted by the models: (i) activity-dependent increases in intracellular sodium concentration directly reduce action potential amplitudes, an effect typically attributed solely to sodium channel inactivation; (ii) extracellular potassium accumulation switches action potential generation from tonic firing to intermittently interrupted output. Thus, individual neurons may respond very differently to the same input stimuli, depending on their recent patterns of activity and/or the current brain-state.

Hebbian plasticity in parallel synaptic pathways: A circuit mechanism for systems memory consolidation.

Systems memory consolidation involves the transfer of memories across brain regions and the transformation of memory content. For example, declarative memories that transiently depend on the hippocampal formation are transformed into long-term memory traces in neocortical networks, and procedural memories are transformed within cortico-striatal networks. These consolidation processes are thought to rely on replay and repetition of recently acquired memories, but the cellular and network mechanisms that mediate the changes of memories are poorly understood. Here, we suggest that systems memory consolidation could arise from Hebbian plasticity in networks with parallel synaptic pathways-two ubiquitous features of neural circuits in the brain. We explore this hypothesis in the context of hippocampus-dependent memories. Using computational models and mathematical analyses, we illustrate how memories are transferred across circuits and discuss why their representations could change. The analyses suggest that Hebbian plasticity mediates consolidation by transferring a linear approximation of a previously acquired memory into a parallel pathway. Our modelling results are further in quantitative agreement with lesion studies in rodents. Moreover, a hierarchical iteration of the mechanism yields power-law forgetting-as observed in psychophysical studies in humans. The predicted circuit mechanism thus bridges spatial scales from single cells to cortical areas and time scales from milliseconds to years.

How to correctly quantify neuronal phase-response curves from noisy recordings.

At the level of individual neurons, various coding properties can be inferred from the input-output relationship of a cell. For small inputs, this relation is captured by the phase-response curve (PRC), which measures the effect of a small perturbation on the timing of the subsequent spike. Experimentally, however, an accurate experimental estimation of PRCs is challenging. Despite elaborate measurement efforts, experimental PRC estimates often cannot be related to those from modeling studies. In particular, experimental PRCs rarely resemble the characteristic theoretical PRC expected close to spike initiation, which is indicative of the underlying spike-onset bifurcation. Here, we show for conductance-based model neurons that the correspondence between theoretical and measured phase-response curve is lost when the stimuli used for the estimation are too large. In this case, the derived phase-response curve is distorted beyond recognition and takes on a generic shape that reflects the measurement protocol and masks the spike-onset bifurcation. We discuss how to identify appropriate stimulus strengths for perturbation and noise-stimulation methods, which permit to estimate PRCs that reliably reflect the spike-onset bifurcation - a task that is particularly difficult if a lower bound for the stimulus amplitude is dictated by prominent intrinsic neuronal noise.

Function and energy consumption constrain neuronal biophysics in a canonical computation: Coincidence detection.

Neural morphology and membrane properties vary greatly between cell types in the nervous system. The computations and local circuit connectivity that neurons support are thought to be the key factors constraining the cells' biophysical properties. Nevertheless, additional constraints can be expected to further shape neuronal design. Here, we focus on a particularly energy-intense system (as indicated by metabolic markers): principal neurons in the medial superior olive (MSO) nucleus of the auditory brainstem. Based on a modeling approach, we show that a trade-off between the level of performance of a functionally relevant computation and energy consumption predicts optimal ranges for cell morphology and membrane properties. The biophysical parameters appear most strongly constrained by functional needs, while energy use is minimized as long as function can be maintained. The key factors that determine model performance and energy consumption are 1) the saturation of the synaptic conductance input and 2) the temporal resolution of the postsynaptic signals as they reach the soma, which is largely determined by active membrane properties. MSO cells seem to operate close to pareto optimality, i.e., the trade-off boundary between performance and energy consumption that is formed by the set of optimal models. Good performance for drastically lower costs could in theory be achieved by small neurons without dendrites, as seen in the avian auditory system, pointing to additional constraints for mammalian MSO cells, including their circuit connectivity.

Cell-Type Specific Phase Precession in Layer II of the Medial Entorhinal Cortex.

The identity of phase-precessing cells in the entorhinal cortex is unknown. Here, we used a classifier derived from cell-attached recordings to separate putative pyramidal cells and putative stellate cells recorded extracellularly in layer II of the medial entorhinal cortex in rats. Using a novel method to identify single runs as temporal periods of elevated spiking activity, we find that both cell types show phase precession but putative stellate cells show steeper slopes of phase precession and larger phase ranges. As the two classes of cells have different projection patterns, phase precession is differentially passed on to different subregions of the hippocampal formation. SIGNIFICANCE STATEMENT: It is a great challenge for neuroscience to reveal the cellular basis of cognitive functions. One such function is the ability to learn and recollect temporal sequences of events. The representation of sequences in the brain is thought to require temporally structured activity of nerve cells. How different types of neurons generate temporally structured activity is currently unknown. In the present study, we use a computational classification procedure to separate different cell types and find that a subpopulation of cells, so-called stellate neurons, exhibits clear temporal coding. Contrary to the stellate cells, pyramidal cells show weaker temporal coding. This discovery sheds light on the cellular basis of temporal coding in the brain.

Spike-timing dependent inhibitory plasticity to learn a selective gating of backpropagating action potentials.

Inhibition is known to influence the forward-directed flow of information within neurons. However, also regulation of backward-directed signals, such as backpropagating action potentials (bAPs), can enrich the functional repertoire of local circuits. Inhibitory control of bAP spread, for example, can provide a switch for the plasticity of excitatory synapses. Although such a mechanism is possible, it requires a precise timing of inhibition to annihilate bAPs without impairment of forward-directed excitatory information flow. Here, we propose a specific learning rule for inhibitory synapses to automatically generate the correct timing to gate bAPs in pyramidal cells when embedded in a local circuit of feedforward inhibition. Based on computational modeling of multi-compartmental neurons with physiological properties, we demonstrate that a learning rule with anti-Hebbian shape can establish the required temporal precision. In contrast to classical spike-timing dependent plasticity of excitatory synapses, the proposed inhibitory learning mechanism does not necessarily require the definition of an upper bound of synaptic weights because of its tendency to self-terminate once annihilation of bAPs has been reached. Our study provides a functional context in which one of the many time-dependent learning rules that have been observed experimentally - specifically, a learning rule with anti-Hebbian shape - is assigned a relevant role for inhibitory synapses. Moreover, the described mechanism is compatible with an upregulation of excitatory plasticity by disinhibition.

Inhibition as a Binary Switch for Excitatory Plasticity in Pyramidal Neurons.

Synaptic plasticity is thought to induce memory traces in the brain that are the foundation of learning. To ensure the stability of these traces in the presence of further learning, however, a regulation of plasticity appears beneficial. Here, we take up the recent suggestion that dendritic inhibition can switch plasticity of excitatory synapses on and off by gating backpropagating action potentials (bAPs) and calcium spikes, i.e., by gating the coincidence signals required for Hebbian forms of plasticity. We analyze temporal and spatial constraints of such a gating and investigate whether it is possible to suppress bAPs without a simultaneous annihilation of the forward-directed information flow via excitatory postsynaptic potentials (EPSPs). In a computational analysis of conductance-based multi-compartmental models, we demonstrate that a robust control of bAPs and calcium spikes is possible in an all-or-none manner, enabling a binary switch of coincidence signals and plasticity. The position of inhibitory synapses on the dendritic tree determines the spatial extent of the effect and allows a pathway-specific regulation of plasticity. With appropriate timing, EPSPs can still trigger somatic action potentials, although backpropagating signals are abolished. An annihilation of bAPs requires precisely timed inhibition, while the timing constraints are less stringent for distal calcium spikes. We further show that a wide-spread motif of local circuits-feedforward inhibition-is well suited to provide the temporal precision needed for the control of bAPs. Altogether, our model provides experimentally testable predictions and demonstrates that the inhibitory switch of plasticity can be a robust and attractive mechanism, hence assigning an additional function to the inhibitory elements of neuronal microcircuits beyond modulation of excitability.

A temperature rise reduces trial-to-trial variability of locust auditory neuron responses.

The neurophysiology of ectothermic animals, such as insects, is affected by environmental temperature, as their body temperature fluctuates with ambient conditions. Changes in temperature alter properties of neurons and, consequently, have an impact on the processing of information. Nevertheless, nervous system function is often maintained over a broad temperature range, exhibiting a surprising robustness to variations in temperature. A special problem arises for acoustically communicating insects, as in these animals mate recognition and mate localization typically rely on the decoding of fast amplitude modulations in calling and courtship songs. In the auditory periphery, however, temporal resolution is constrained by intrinsic neuronal noise. Such noise predominantly arises from the stochasticity of ion channel gating and potentially impairs the processing of sensory signals. On the basis of intracellular recordings of locust auditory neurons, we show that intrinsic neuronal variability on the level of spikes is reduced with increasing temperature. We use a detailed mathematical model including stochastic ion channel gating to shed light on the underlying biophysical mechanisms in auditory receptor neurons: because of a redistribution of channel-induced current noise toward higher frequencies and specifics of the temperature dependence of the membrane impedance, membrane potential noise is indeed reduced at higher temperatures. This finding holds under generic conditions and physiologically plausible assumptions on the temperature dependence of the channels' kinetics and peak conductances. We demonstrate that the identified mechanism also can explain the experimentally observed reduction of spike timing variability at higher temperatures.

Src-kinase inhibitors sensitize human cells of myeloid origin to Toll-like-receptor-induced interleukin 12 synthesis.

Src-kinase inhibitors hold great potential as targeted therapy against malignant cells. However, such inhibitors may also affect nonmalignant cells and cause pronounced off-target effects. We investigated the role of the dual kinase inhibitor dasatinib on human myeloid cells. Dasatinib is clinically used for the treatment of bcr/abl⁺ leukemias because it blocks the mutated tyrosine kinase abl. To understand its effect on the development of antigen-specific T-cell responses, we assessed antigen-specific priming of human, naïve T cells. In surprising contrast to the direct inhibition of T-cell activation by dasatinib, pretreatment of maturing dendritic cells (DCs) with dasatinib strongly enhanced their stimulatory activity. This effect strictly depended on the activating DC stimulus and led to enhanced interleukin 12 (IL-12) production and T-cell responses of higher functional avidity. Src-kinase inhibitors, and not conventional tyrosine kinase inhibitors, increased IL-12 production in several cell types of myeloid origin, such as monocytes and classical or nonclassical DCs. Interestingly, only human cells, but not mouse or macaques DCs, were affected. These data highlight the potential immunostimulatory capacity of a group of novel drugs, src-kinase inhibitors, thereby opening new opportunities for chemoimmunotherapy. These data also provide evidence for a regulatory role of src kinases in the activation of myeloid cells.

Information filtering in resonant neurons.

Neuronal information transmission is frequency specific. In single cells, a band-pass like frequency preference can arise from the subthreshold dynamics of the membrane potential, shaped by properties of the cell's membrane and its ionic channels. In these cases, a cell is termed resonant and its membrane impedance spectrum exhibits a peak at non-vanishing frequencies. Here, we show that this frequency selectivity of neuronal response amplitudes need not translate into a similar frequency selectivity of information transfer. In particular, neurons with resonant but linear subthreshold voltage dynamics (without threshold) do not show a resonance of information transfer at the level of subthreshold voltage; the corresponding coherence has low-pass characteristics. Interestingly, we find that when combined with nonlinearities, subthreshold resonances do shape the frequency dependence of coherence and the peak in the subthreshold impedance translates to a peak in the coherence function. In other words, the nonlinearity inherent to spike generation allows a subthreshold impedance resonance to shape a resonance of voltage-based information transfer. We demonstrate such nonlinearity-mediated band-pass filtering of information at frequencies close to the subthreshold impedance resonance in three different model systems: the resonate-and-fire model, the conductance-based Morris-Lecar model, and linear resonant dynamics combined with a simple static nonlinearity. In the spiking neuron models, the band-pass filtering is most pronounced for low firing rates and a high variability of interspike intervals, similar to the spiking statistics observed in vivo. We show that band-pass filtering is achieved by reducing information transfer over low-frequency components and, consequently, comes along with an overall reduction of information rate. Our work highlights the crucial role of nonlinearities for the frequency dependence of neuronal information transmission.

Firing-rate resonances in the peripheral auditory system of the cricket, Gryllus bimaculatus.

In many communication systems, information is encoded in the temporal pattern of signals. For rhythmic signals that carry information in specific frequency bands, a neuronal system may profit from tuning its inherent filtering properties towards a peak sensitivity in the respective frequency range. The cricket Gryllus bimaculatus evaluates acoustic communication signals of both conspecifics and predators. The song signals of conspecifics exhibit a characteristic pulse pattern that contains only a narrow range of modulation frequencies. We examined individual neurons (AN1, AN2, ON1) in the peripheral auditory system of the cricket for tuning towards specific modulation frequencies by assessing their firing-rate resonance. Acoustic stimuli with a swept-frequency envelope allowed an efficient characterization of the cells' modulation transfer functions. Some of the examined cells exhibited tuned band-pass properties. Using simple computational models, we demonstrate how different, cell-intrinsic or network-based mechanisms such as subthreshold resonances, spike-triggered adaptation, as well as an interplay of excitation and inhibition can account for the experimentally observed firing-rate resonances. Therefore, basic neuronal mechanisms that share negative feedback as a common theme may contribute to selectivity in the peripheral auditory pathway of crickets that is designed towards mate recognition and predator avoidance.

Grid cells in rat entorhinal cortex encode physical space with independent firing fields and phase precession at the single-trial level.

When a rat moves, grid cells in its entorhinal cortex become active in multiple regions of the external world that form a hexagonal lattice. As the animal traverses one such "firing field," spikes tend to occur at successively earlier theta phases of the local field potential. This phenomenon is called phase precession. Here, we show that spike phases provide 80% more spatial information than spike counts and that they improve position estimates from single neurons down to a few centimeters. To understand what limits the resolution and how variable spike phases are across different field traversals, we analyze spike trains run by run. We find that the multiple firing fields of a grid cell operate as independent elements for encoding physical space. In addition, phase precession is significantly stronger than the pooled-run data suggest. Despite the inherent stochasticity of grid-cell firing, phase precession is therefore a robust phenomenon at the single-trial level, making a theta-phase code for spatial navigation feasible.

Development and validation of a fully GMP-compliant production process of autologous, tumor-lysate-pulsed dendritic cells.

BACKGROUND AND AIMS: One of the major challenges of dendritic cell (DC) vaccination is the establishment of harmonized DC production protocols. Here, we report the transfer and validation of a successfully used open DC manufacturing method into a closed system, good manufacturing practice (GMP)-compatible protocol. METHODS: All production steps (lysate generation, monocyte selection, DC culture and cryopreservation) were standardized and validated. RESULTS: Tumor lysate was characterized by histology, mechanically homogenized and avitalized. This preparation yielded a median of 58 ± 21 µg protein per milligram of tumor tissue. Avitality was determined by trypan blue staining and confirmed in an adenosine triphosphate release assay. Patient monocytes were isolated by elutriation or CD14 selection, which yielded equivalent results. DCs were subsequently differentiated in Teflon bags for an optimum of 7 days in CellGro medium supplemented with interleukin (IL)-4 and granulocyte macrophage colony stimulating factor and then matured for 48 h in tumor necrosis factor-α and IL-1ß after pulsing with tumor lysate. This protocol resulted in robust and reproducible upregulation of DC maturation markers such as cluster of differentiation (CD)80, CD83, CD86, human leukocyte antigen-DR and DC-SIGN. Functionality of these DCs was shown by directed migration toward C-C motif chemokine ligand 19/21, positive T-cell stimulatory capacity and the ability to prime antigen-specific T cells from naive CD8(+) T cells. Phenotype stability, vitality and functionality of DCs after cryopreservation, thawing and washing showed no significant loss of function. Comparison of clinical data from 146 patients having received vaccinations with plate-adherence versus GMP-grade DCs showed no inferiority of the latter. CONCLUSIONS: Our robust, validated and approved protocol for DC manufacturing forms the basis for a harmonized procedure to produce cancer vaccines, which paves the way for larger multi-center clinical trials.

Dynamics and reliability of bistable neurons driven with time-dependent stimuli.

The reliability of a spiking neuron depends on the frequency content of the driving input signal. Previous studies have shown that well above threshold, regularly firing neurons generate reliable responses when the input signal resonates with the firing frequency of the cell. Instead, well below threshold, reliable responses are obtained when the input frequency resonates with the subthreshold oscillations of the neuron. Previous theories, however, provide no clear prediction for the input frequency giving rise to maximally reliable spiking at threshold, which is probably the most relevant firing regime in mammalian cortex under physiological conditions. In particular, when the firing onset is governed by a subcritical Hopf bifurcation, the frequency of subthreshold oscillations often differs from the firing rate at threshold. The predictions of previous studies, hence, cannot be smoothly merged at threshold. Here we explore the behavior of reliability in bistable neurons near threshold using three types of driving stimuli: constant, periodic, and stochastic. We find that the two natural frequencies of the system, associated with the two coexisting attractors, provide a rich variety of possible locking modes with the external signal. Reliability is determined by the sensitivity to noise of each locking mode and by the transition probabilities between modes. Noise increases the amount of spike time jitter, and minimal jitter is obtained for input frequencies coinciding with the suprathreshold firing rate of the cell. In addition, noise may either enhance or inhibit transitions between the two attractors, depending on the input frequency. The dual role played by noise in bistable systems implies that reliability is determined by a delicate balance between spike time jitter and the rate of transitions between attractors.

Efficient transformation of an auditory population code in a small sensory system.

Optimal coding principles are implemented in many large sensory systems. They include the systematic transformation of external stimuli into a sparse and decorrelated neuronal representation, enabling a flexible readout of stimulus properties. Are these principles also applicable to size-constrained systems, which have to rely on a limited number of neurons and may only have to fulfill specific and restricted tasks? We studied this question in an insect system--the early auditory pathway of grasshoppers. Grasshoppers use genetically fixed songs to recognize mates. The first steps of neural processing of songs take place in a small three-layer feed-forward network comprising only a few dozen neurons. We analyzed the transformation of the neural code within this network. Indeed, grasshoppers create a decorrelated and sparse representation, in accordance with optimal coding theory. Whereas the neuronal input layer is best read out as a summed population, a labeled-line population code for temporal features of the song is established after only two processing steps. At this stage, information about song identity is maximal for a population decoder that preserves neuronal identity. We conclude that optimal coding principles do apply to the early auditory system of the grasshopper, despite its size constraints. The inputs, however, are not encoded in a systematic, map-like fashion as in many larger sensory systems. Already at its periphery, part of the grasshopper auditory system seems to focus on behaviorally relevant features, and is in this property more reminiscent of higher sensory areas in vertebrates.

Linking dynamical and functional properties of intrinsically bursting neurons.

Several studies have shown that bursting neurons can encode information in the number of spikes per burst: As the stimulus varies, so does the length of individual bursts. There presented stimuli, however, vary substantially among different sensory modalities and different neurons.The goal of this paper is to determine which kind of stimulus features can be encoded in burst length, and how those features depend on the mathematical properties of the underlying dynamical system.We show that the initiation and termination of each burst is triggered by specific stimulus features whose temporal characteristsics are determined by the types of bifurcations that initiate and terminate firing in each burst. As only a few bifurcations are possible, only a restricted number of encoded features exists. Here we focus specifically on describing parabolic, square-wave and elliptic bursters. We find that parabolic bursters, whose firing is initiated and terminated by saddle-node bifurcations, behave as prototypical integrators: Firing is triggered by depolarizing stimuli, and lasts for as long as excitation is prolonged. Elliptic bursters, contrastingly, constitute prototypical resonators, since both the initiating and terminating bifurcations possess well-defined oscillation time scales. Firing is therefore triggered by stimulus stretches of matching frequency and terminated by a phase-inversion in the oscillation. The behavior of square-wave bursters is somewhat intermediate, since they are triggered by a fold bifurcation of cycles of well-defined frequency but are terminated by a homoclinic bifurcation lacking an oscillating time scale. These correspondences show that stimulus selectivity is determined by the type of bifurcations. By testing several neuron models, we also demonstrate that additional biological properties that do not modify the bifurcation structure play a minor role in stimulus encoding. Moreover, we show that burst-length variability (and thereby, the capacity to transmit information) depends on a trade-off between the variance of the external signal driving the cell and the strength of the slow internal currents modulating bursts. Thus, our work explicitly links the computational properties of bursting neurons to the mathematical properties of the underlying dynamical systems.

KCC2 reverse mode helps to clear postsynaptically released potassium at glutamatergic synapses.

Extracellular potassium [K+]o elevation during synaptic activity retrogradely modifies presynaptic release and astrocytic uptake of glutamate. Hence, local K+ clearance and replenishment mechanisms are crucial regulators of glutamatergic transmission and plasticity. Based on recordings of astrocytic inward rectifier potassium current IKir and K+-sensitive electrodes as sensors of [K+]o as well as on in silico modeling, we demonstrate that the neuronal K+-Cl- co-transporter KCC2 clears local perisynaptic [K+]o during synaptic excitation by operating in an activity-dependent reversed mode. In reverse mode, KCC2 replenishes K+ in dendritic spines and complements clearance of [K+]o, therewith attenuating presynaptic glutamate release and shortening LTP. We thus demonstrate a physiological role of KCC2 in neuron-glial interactions and regulation of synaptic signaling and plasticity through the uptake of postsynaptically released K+.