Synaptic Conductance Changes Research Articles

PEDOT:PSS Wire: A Two-Terminal Synaptic Device for Operation in Electrolyte and Saline Solutions.

Synaptic devices, which are designed to emulate the synaptic functions of neurons, have recently gained attention as key elements in the development of neuromorphic hardware. To date, most synaptic devices utilizing conductive polymer materials, particularly poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), have been designed as three-terminal devices. Nevertheless, a recent study revealed that a single PEDOT:PSS wire can function as a two-terminal synaptic device through additional polymerization, which creates asymmetry in the wire diameter between the anode and cathode. Owing to its high biocompatibility, PEDOT is considered a promising candidate for use in clinical information-processing devices. However, previous studies examined the synaptic function of PEDOT:PSS only in PSS solutions. Therefore, the performance of PEDOT:PSS wires in other solutions, such as physiological saline solutions, remains unknown. Herein, we investigated the effects of operating environmental conditions (including phosphate-buffered saline (PBS)) on the synaptic functions of the asymmetric PEDOT:PSS wire. Our results indicate that the synaptic conductance change in the PEDOT:PSS wire occurred in all investigated aqueous electrolyte solutions. Moreover, we revealed the relationship between the synaptic conductance change behavior and the molecular properties of the electrolyte ions. Furthermore, the waveform of the conductance change can be controlled by adjusting the conditions for wire asymmetrization. These results demonstrate that the PEDOT:PSS wire exhibits a synaptic conductance change, yielding a waveform suitable for machine learning, even under wet conditions (i.e., in any electrolyte solution, including PBS). Therefore, PEDOT:PSS wire is a promising material for two-terminal synaptic devices applicable in clinical studies.

Propagation of Oscillations in the Indirect Pathway of the Basal Ganglia.

Oscillatory signals propagate in the basal ganglia from prototypic neurons in the external globus pallidus (GPe) to their target neurons in the substantia nigra pars reticulata (SNr), internal pallidal segment, and subthalamic nucleus. Neurons in the GPe fire spontaneously, so oscillatory input signals can be encoded as changes in timing of action potentials within an ongoing spike train. When GPe neurons were driven by an oscillatory current in male and female mice, these spike-timing changes produced spike-oscillation coherence over a range of frequencies extending at least to 100 Hz. Using the known kinetics of the GPe→SNr synapse, we calculated the postsynaptic currents that would be generated in SNr neurons from the recorded GPe spike trains. The ongoing synaptic barrage from spontaneous firing, frequency-dependent short-term depression, and stochastic fluctuations at the synapse embed the input oscillation into a noisy sequence of synaptic currents in the SNr. The oscillatory component of the resulting synaptic current must compete with the noisy spontaneous synaptic barrage for control of postsynaptic SNr neurons, which have their own frequency-dependent sensitivities. Despite this, SNr neurons subjected to synaptic conductance changes generated from recorded GPe neuron firing patterns also became coherent with oscillations over a broad range of frequencies. The presynaptic, synaptic, and postsynaptic frequency sensitivities were all dependent on the firing rates of presynaptic and postsynaptic neurons. Firing rate changes, often assumed to be the propagating signal in these circuits, do not encode most oscillation frequencies, but instead determine which signal frequencies propagate effectively and which are suppressed.SIGNIFICANCE STATEMENT Oscillations are present in all the basal ganglia nuclei, include a range of frequencies, and change over the course of learning and behavior. Exaggerated oscillations are a hallmark of basal ganglia pathologies, and each has a specific frequency range. Because of its position as a hub in the basal ganglia circuitry, the globus pallidus is a candidate origin for oscillations propagating between nuclei. We imposed low-amplitude oscillations on individual globus pallidus neurons at specific frequencies and measured the coherence between the oscillation and firing as a function of frequency. We then used these responses to measure the effectiveness of oscillatory propagation to other basal ganglia nuclei. Propagation was effective for oscillation frequencies as high as 100 Hz.

Strong and reliable synaptic communication between pyramidal neurons in adult human cerebral cortex.

Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3-4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

Spike and burst coding in thalamocortical relay cells.

Mammalian thalamocortical relay (TCR) neurons switch their firing activity between a tonic spiking and a bursting regime. In a combined experimental and computational study, we investigated the features in the input signal that single spikes and bursts in the output spike train represent and how this code is influenced by the membrane voltage state of the neuron. Identical frozen Gaussian noise current traces were injected into TCR neurons in rat brain slices as well as in a validated three-compartment TCR model cell. The resulting membrane voltage traces and spike trains were analyzed by calculating the coherence and impedance. Reverse correlation techniques gave the Event-Triggered Average (ETA) and the Event-Triggered Covariance (ETC). This demonstrated that the feature selectivity started relatively long before the events (up to 300 ms) and showed a clear distinction between spikes (selective for fluctuations) and bursts (selective for integration). The model cell was fine-tuned to mimic the frozen noise initiated spike and burst responses to within experimental accuracy, especially for the mixed mode regimes. The information content carried by the various types of events in the signal as well as by the whole signal was calculated. Bursts phase-lock to and transfer information at lower frequencies than single spikes. On depolarization the neuron transits smoothly from the predominantly bursting regime to a spiking regime, in which it is more sensitive to high-frequency fluctuations. The model was then used to elucidate properties that could not be assessed experimentally, in particular the role of two important subthreshold voltage-dependent currents: the low threshold activated calcium current (IT) and the cyclic nucleotide modulated h current (Ih). The ETAs of those currents and their underlying activation/inactivation states not only explained the state dependence of the firing regime but also the long-lasting concerted dynamic action of the two currents. Finally, the model was used to investigate the more realistic “high-conductance state”, where fluctuations are caused by (synaptic) conductance changes instead of current injection. Under “standard” conditions bursts are difficult to initiate, given the high degree of inactivation of the T-type calcium current. Strong and/or precisely timed inhibitory currents were able to remove this inactivation.

A kainate receptor subunit promotes the recycling of the neuron-specific K+-Cl− co-transporter KCC2 in hippocampal neurons

Synaptic inhibition depends on a transmembrane gradient of chloride, which is set by the neuron-specific K+-Cl- co-transporter KCC2. Reduced KCC2 levels in the neuronal membrane contribute to the generation of epilepsy, neuropathic pain, and autism spectrum disorders; thus, it is important to characterize the mechanisms regulating KCC2 expression. In the present study, we determined the role of KCC2-protein interactions in regulating total and surface membrane KCC2 expression. Using quantitative immunofluorescence in cultured mouse hippocampal neurons, we discovered that the kainate receptor subunit GluK2 and the auxiliary subunit Neto2 significantly increase the total KCC2 abundance in neurons but that GluK2 exclusively increases the abundance of KCC2 in the surface membrane. Using a live cell imaging assay, we further determined that KCC2 recycling primarily occurs within 1-2 h and that GluK2 produces an ∼40% increase in the amount of KCC2 recycled to the membrane during this time period. This GluK2-mediated increase in surface recycling translated to a significant increase in KCC2 expression in the surface membrane. Moreover, we found that KCC2 recycling is enhanced by protein kinase C-mediated phosphorylation of the GluK2 C-terminal residues Ser-846 and Ser-868. Lastly, using gramicidin-perforated patch clamp recordings, we found that the GluK2-mediated increase in KCC2 recycling to the surface membrane translates to a hyperpolarization of the reversal potential for GABA (EGABA). In conclusion, our results have revealed a mechanism by which kainate receptors regulate KCC2 expression in the hippocampus.

Inferring presynaptic population spiking from single-trial membrane potential recordings

BackgroundThe time-varying membrane potential of a cortical neuron contains important information about the network activity. Extracting this information requires separating excitatory and inhibitory synaptic inputs from single-trial membrane potential recordings without averaging across trials. New methodWe propose a method to extract the time course of excitatory and inhibitory synaptic inputs to a neuron from a single-trial membrane potential recording. The method takes advantage of the differences in the time constants and the reversal potentials of the excitatory and inhibitory synaptic currents, which allows the untangling of the two conductance types. ResultsWe evaluate the applicability of the method on a leaky integrate-and-fire model neuron and find high quality of estimation of excitatory synaptic conductance changes and presynaptic population spikes. Application of the method to a real cortical neuron with known synaptic inputs in a brain slice returns high-quality estimation of the time course of the excitatory synaptic conductance. Application of the method to membrane potential recordings from a cortical pyramidal neuron of an intact brain reveals complex network activity. Comparison with existing methodsExisting methods are based on repeated trials and thus are limited to estimating the statistical features of synaptic conductance changes, or, when based on single trials, are limited to special cases, have low temporal resolution, or are impractically complicated. ConclusionsWe propose and test an efficient method for estimating the full time course of excitatory and inhibitory synaptic conductances from single-trial membrane potential recordings. The method is sufficiently simple to ensure widespread use in neuroscience.

Regulation of AMPA receptor phosphorylation by the neuropeptide PACAP38

Dynamic changes in synaptic strength are thought to be critical for higher brain function such as learning and memory. Alterations in synaptic strength can result from modulation of AMPA receptor (AMPAR) function and trafficking to synaptic sites. The phosphorylation state of AMPAR subunits is one mechanism by which cells regulate receptor function and trafficking. Receptor phosphorylation is in turn regulated by extracellular signals; these include neuronal activity, neuropeptides, and neuromodulators such as dopamine and norepinephrine (NE). Although numerous studies have reported that the neuropeptide pituitary adenylate cyclase activating polypeptide 38 (PACAP38) alters hippocampal CA1 synaptic strength and GluA1 synaptic localization, its effect on AMPAR phosphorylation state has not been explored. We determined that PACAP38 stimulation of hippocampal cultures increased phosphorylation of S845, and decreased phosphorylation of T840 on the GluA1 AMPAR subunit. Increases in GluA1 S845 phosphorylation primarily occurred via PAC1 and VPAC2 receptor activation, whereas a reduction in GluA1 T840 phosphorylation was largely driven by PAC1 receptor activation and to a lesser extent by VPAC1 and VPAC2 receptor activation. GluA1 S845 phosphorylation could be blocked by a PKA inhibitor, and GluA1 T840 dephosphorylation could be blocked by a protein phosphatase 1/2A (PP1/PP2A) inhibitor and was partly blocked by a NMDA receptor (NMDAR) antagonist. These results demonstrate that the neuropeptide PACAP38 inversely regulates the phosphorylation of two distinct sites on GluA1 and may play an important role modulating AMPAR function and synaptic plasticity in the brain.

Calcium control of triphasic hippocampal STDP

Synaptic plasticity is believed to represent the neural correlate of mammalian learning and memory function. It has been demonstrated that changes in synaptic conductance can be induced by approximately synchronous pairings of pre- and post- synaptic action potentials delivered at low frequencies. It has also been established that NMDAr-dependent calcium influx into dendritic spines represents a critical signal for plasticity induction, and can account for this spike-timing dependent plasticity (STDP) as well as experimental data obtained using other stimulation protocols. However, subsequent empirical studies have delineated a more complex relationship between spike-timing, firing rate, stimulus duration and post-synaptic bursting in dictating changes in the conductance of hippocampal excitatory synapses. Here, we present a detailed biophysical model of single dendritic spines on a CA1 pyramidal neuron, describe the NMDAr-dependent calcium influx generated by different stimulation protocols, and construct a parsimonious model of calcium driven kinase and phosphatase dynamics that dictate the probability of stochastic transitions between binary synaptic weight states in a Markov model. We subsequently demonstrate that this approach can account for a range of empirical observations regarding the dynamics of synaptic plasticity induced by different stimulation protocols, under regimes of pharmacological blockade and metaplasticity. Finally, we highlight the strengths and weaknesses of this parsimonious, unified computational synaptic plasticity model, discuss differences between the properties of cortical and hippocampal plasticity highlighted by the experimental literature, and the manner in which further empirical and theoretical research might elucidate the cellular basis of mammalian learning and memory function.

Opposing effects of intrinsic conductance and correlated synaptic input on Vm-fluctuations during network activity

Neurons often receive massive concurrent bombardment of synaptic inhibition and excitation during functional network activity. This increases membrane conductance and causes fluctuations in membrane potential (Vm) and spike timing. The conductance increase is commonly attributed to synaptic conductance, but also includes the intrinsic conductances recruited during network activity. These two sources of conductance have contrasting dynamic properties at sub-threshold membrane potentials. Synaptic transmitter gated conductance changes abruptly and briefly with each presynaptic action potential. If the spikes arrive at random times the changes in synaptic conductance are therefore stochastic and rapid during intense network activity. In comparison, sub-threshold intrinsic conductances vary smoothly in time. In the present study this discrepancy is investigated using two conductance-based models: a (1) compartment model and a (2) compartment with realistic slow intrinsic conductances. We examine the effects of varying the relative contributions of non-fluctuating intrinsic conductance with fluctuating concurrent inhibitory and excitatory synaptic conductance. For given levels of correlation in the synaptic input we find that the magnitude of the membrane fluctuations uniquely determines the relative contribution of synaptic and intrinsic conductance. We also quantify how Vm-fluctuations vary with synaptic correlations for fixed ratios of synaptic and intrinsic conductance. Interestingly, the levels of Vm -fluctuations and conductance observed experimentally during functional network activity leave little room for intrinsic conductance to contribute. Even without intrinsic conductances the variance in Vm -fluctuations can only be explained by a high degree of correlated firing among presynaptic neurons.

Climbing-fiber induced state transitions in cerebellar Purkinje cells are controlled by synaptic conductance changes

Purkinje cells have been previously modeled as a systemundergoing a saddle-node bifurcation of fixed pointsfrom rest to firing and a saddle homoclinic orbit bifur-cation from firing to rest. In vitro, this dynamical struc-ture is a result of the neuron’s intrinsic membraneproperties and is associated with bistability within a lim-ited range of low firing frequencies, where a unidirec-tional climbing fiber (CF) input is able to toggle the cellbetween a firing (“up”)andrest(“down”)state.Weidentified several factors that contribute to bistabilityand the ability for a unidirectional input (CF) to togglecell output, including a slow K+ current activated duringspike discharge or followingsynaptic depolarizations.However, input conditions that determine the probabil-ity for a Purkinje cell to express bistabilityin vivo havenot been determined. A key difference in vivo is the pre-sence of tonic background input to the dendrites fromparallel fiber (PF) and stellate cell inputs. We tested thehypothesis that dendritic inputs control the dynamics ofPurkinje cell firing, and can thus regulate the ability forCFs to induce toggling of Purkinje cell output.Presentation of mixed excitatory and inhibitory dendri-tic current noise (I-noise) or conductance noise (g-noise)to a two-compartment 5-equation model of the Purkinjeneuron had differing effects on spike output. Mixed I-noise increased the probability of observing CF-evokedtransitions to a down state whether the model was in thelow frequency-bistable regime or not. The size and timecourse of the currents associated with different statetransitions suggested that properly timed PF and/or stel-late cell inputs could affect the ability for CFs to invokePurkinje cell transitions. However, conductance noiseprevented any CF-evoked transitions and the model washighly sensitive to the E:I ratio. Spike trains with physio-logical mean frequencies and high coefficient of variation(CV) were also found. Spike triggered averages duringg-noise revealed that the spikes were being driven bysynaptic inputs and not intrinsic dynamics, indicating ashift in computational properties between high and lowconductance states.ConclusionsHere we show that bistabilityinaPurkinjeneuroncanbe controlled by the amount of synaptic input itreceives. Of the two types of noise we used, I-noisecould cause spontaneous state transitions, but g-noisecould not, suggesting that CF-associated toggling wouldnot occur in high conductance states. These resultscould explain the discrepancy between in vivo and in vitrorecordings regarding CF-induced state transitions.

Integration of Cellular Metabolism and Membrane Excitability in Cerebellar Purkinje Neurons

Calcium and membrane physiology are crucial to cerebellar Purkinje neuron function. Purkinje cell physiology involves phosphoinositide/calcium signaling and calcium influx through voltage-gated calcium channels, as well as potassium efflux through (i) voltage-gated, and (ii) calcium-activated voltage-gated channels (primarily the BK channel). The interaction between phosphoinositide-induced calcium signaling and calcium-activated/voltage-gated potassium channels have not been explored extensively. We have developed computational models to explore the integration of these mechanisms. We used an electrophysiological model in NEURON to parameterize a compartmental Virtual Cell (VCell) model. We then combined our published calcium metabolism model (created in VCell) with the electrophysiological model. We investigated the influence of IP3R1-mediated calcium release from smooth endoplasmic reticulum close to the plasma membrane on the activity of the BK channel and thus on membrane potential. The model predicts that supralinear IP3R1-mediated calcium release into a submembrane shell can activate BK channels. When coupled with synaptic conductance changes, this activation of the BK channels increases the rate of repolarization (RR) of the spine. As the voltage changes in the spine propagate to the soma, the corresponding RR in the soma is also increased. Simulation of IP3R1 ko abolishes any increase in the RR in both the spine and the soma. Reduced IP3R1 abundance (as found in some cerebellar ataxias; in model, 10% - 50% of the original value), almost completely abolishes any increase in the RR, in both spine and soma. Increasing the sensitivity of IP3R1 to IP3 restores normal IP3R1-mediated calcium, and restores increased activation of the BK channels. The resulting RR of both the spine and the soma are also restored. These results suggest that the BK channel may play a role in integrating signals from cellular metabolism and membrane excitability. (Supported by NIH P41 RR013186)

Generating oscillatory bursts from a network of regular spiking neurons without inhibition

Avian nucleus isthmi pars parvocellularis (Ipc) neurons are reciprocally connected with the layer 10 (L10) neurons in the optic tectum and respond with oscillatory bursts to visual stimulation. Our in vitro experiments show that both neuron types respond with regular spiking to somatic current injection and that the feedforward and feedback synaptic connections are excitatory, but of different strength and time course. To elucidate mechanisms of oscillatory bursting in this network of regularly spiking neurons, we investigated an experimentally constrained model of coupled leaky integrate-and-fire neurons with spike-rate adaptation. The model reproduces the observed Ipc oscillatory bursting in response to simulated visual stimulation. A scan through the model parameter volume reveals that Ipc oscillatory burst generation can be caused by strong and brief feedforward synaptic conductance changes. The mechanism is sensitive to the parameter values of spike-rate adaptation. In conclusion, we show that a network of regular-spiking neurons with feedforward excitation and spike-rate adaptation can generate oscillatory bursting in response to a constant input.

Consequences of non-uniform active currents in dendrites

Thalamocortical (TC) neurons lead double lives: In a depolarized state near threshold excitatory synaptic input evokes regular spiking that faithfully “relays” information to the cortex, but when the cell is hyperpolarized, the same excitatory input can lead to a low-threshold spike (LTS), triggered by low the threshold calcium T-currents (Figure ​(Figure1).1). LTSs in TC cells occur during sleep, when the membrane potential is hyperpolarized as a consequence of reduced levels of neuromodulatory inputs and the opening of potassium currents. The LTSs are prominent features of sleep spindles, but can also appear in states of alertness. We have known that TC cell have this dual function since it was first reported by Jahnsen and Llinas (1984), but only recently has the distribution of T-currents in the TC cells been explored. Figure 1 Sleep, epilepsy and thalamic reticular inhibitory neurons. Steriade M. Cortical, reticular and thalamocortical neurons showing connectivity (+ excitation, − inhibition), intracellular recordings and anatomical reconstructions from cats. Cortical ... T-current recorded from the somas of dissociated TC cells lacking dendrites have much smaller amplitudes than in cells recorded from thalamic slices, which suggests that the T-channels are mainly dendritic (Destexhe et al., 1998). Are the T-currents distributed uniformly in the dendrites, or are they concentrated more proximally or more distally? In this issue, Zomorrodi et al. (2008) have modeled these possibilities and concluded that the lowest threshold LTS occurs when the T-current are located proximally. Most of their simulations were based on a 3 compartment model, consisting of a soma, a proximal dendritic segment and a distal dendritic segment. They also reconstructed a complete TC cell and used simulations of the more accurate morphology to show that the results were even more robust than for the 3 compartment model. Confirmation of the prediction that T-current is concentrated in the proximal dendrites of TC cells awaits high-resolution electron microscopic imaging of the Cav3.1 and Cav3.3 T-channels. In neurons of the reticular nucleus of the thalamus, which also exhibit an LTS, the T-current is concentrated in the distal dendrites (Kovacs et al., 2009), where they generate a prolonged LTS (Destexhe et al. 1996). Although the proximal localization of T-currents in the dendrites of TC cells may require the least current to trigger an LTS when current is injected in the soma, it is not clear whether this is also true for synaptic conductance changes in the dendrites. Another open issue is whether single dendrites behave like functional units, as occurs in hippocampal cells (Gasparini et al., 2004)? If so, input from a cluster of synapses on a single dendrite could be sufficient to trigger an LTS. Or is the TC cell electrically compact? In a previous compartmental model of the TC cell (Destexhe et al., 1998), reconstructed from a 200 μm slice, the dendrites were much shorter and more electrically compact than the reconstructed TC cell in the current study, which had dendrites extending 400 μm from the soma (Zomorrodi et al., 2008). The H-current, a non-specific cation current that is activated by membrane hyperpolarization, also participates in the LTS in TC cells, particularly during sleep spindles. The effects of its distribution within the TC cell could also be studied with compartmental models, in conjunction with the distribution of the T-currents. The optimal distributions of these currents may not be independent of each other, so they need to be jointly varied. The calcium that enters the neuron during an LTS must be internally bound or extruded to maintain the equilibrium of free calcium in the cell in the long term. This is accomplished by Ca2+/Na+ metabolic exchangers in the plasma membrane. Reducing the number of T-channels needed to trigger an LTS would reduce the number of calcium ions that need to be extruded later, and hence would reduce the energy that the TC cell must expend to function. In the hippocampus, nonmyelinated axons have a fast sodium current and delayed potassium current, which reduces the overlap of the currents and minimizes the cost of an action potential (Alle et al., 2009). Similarly, pyramidal neurons and fast-spiking interneurons in the cerebral cortex also minimize energy expenditure for the patterns of action potentials they generate in vivo (Hasenstaub et al. 2009). This may be a general principle for neural information processing systems (Laughlin et al., 1998; Laughlin and Sejnowski, 2003).

Asymmetric Operation of the Locomotor Central Pattern Generator in the Neonatal Mouse Spinal Cord

The rhythmic voltage oscillations in motor neurons (MNs) during locomotor movements reflect the operation of the pre-MN central pattern generator (CPG) network. Recordings from MNs can thus be used as a method to deduct the organization of CPGs. Here, we use continuous conductance measurements and decomposition methods to quantitatively assess the weighting and phase tuning of synaptic inputs to different flexor and extensor MNs during locomotor-like activity in the isolated neonatal mice lumbar spinal cord preparation. Whole cell recordings were obtained from 22 flexor and 18 extensor MNs in rostral and caudal lumbar segments. In all flexor and the large majority of extensor MNs the extracted excitatory and inhibitory synaptic conductances alternate but with a predominance of inhibitory conductances, most pronounced in extensors. These conductance changes are consistent with a "push-pull" operation of locomotor CPG. The extracted excitatory and inhibitory synaptic conductances varied between 2 and 56% of the mean total conductance. Analysis of the phase tuning of the extracted synaptic conductances in flexor and extensor MNs in the rostral lumbar cord showed that the flexor-phase-related synaptic conductance changes have sharper locomotor-phase tuning than the extensor-phase-related conductances, suggesting a modular organization of premotor CPG networks consisting of reciprocally coupled, but differently composed, flexor and extensor CPG networks. There was a clear difference between phase tuning in rostral and caudal MNs, suggesting a distinct operation of CPG networks in different lumbar segments. The highly asymmetric features were preserved throughout all ranges of locomotor frequencies investigated and with different combinations of locomotor-inducing drugs. The asymmetric nature of CPG operation and phase tuning of the conductance profiles provide important clues to the organization of the rodent locomotor CPG and are compatible with a multilayered and distributed structure of the network.

Background Synaptic Activity Is Sparse in Neocortex

Neurons are continually exposed to background synaptic activity in vivo. This is thought to influence neural information processing, but background levels of excitation and inhibition remain controversial. Here we show, using whole-cell recordings in anesthetized rats, that spontaneous depolarizations ("Up states") in neocortical pyramidal neurons are driven by sparse, mostly excitatory synaptic activity (less than five inputs per millisecond; approximately 10% inhibitory). The mean synaptic conductance change is small (<10 nS at the soma) and opposed by anomalous rectification, resulting in a net increase in input resistance during Up states. These conditions enhance the effectiveness of each synapse at depolarized potentials. Hence, neocortical networks are relatively quiet at rest, and the effect of synaptic background is weaker than previously thought.

Synaptic plasticity with discrete state synapses

Experimental observations on synaptic plasticity at individual glutamatergic synapses from the CA3 Shaffer collateral pathway onto CA1 pyramidal cells in the hippocampus suggest that the transitions in synaptic strength occur among discrete levels at individual synapses [C. C. H. Petersen, Proc. Natl. Acad. Sci. USA 85, 4732 (1998); O'Connor, Wittenberg, and Wang, D. H. O'Connor, Proc. Natl. Acad. Sci. USA (to be published); J. M. Montgomery and D. V. Madison, Trends Neurosci. 27, 744 (2004)]. This happens for both long term potentiation (LTP) and long term depression (LTD) induction protocols. O'Connor, Wittenberg, and Wang have argued that three states would account for their observations on individual synapses in the CA3-CA1 pathway. We develop a quantitative model of this three-state system with transitions among the states determined by a competition between kinases and phosphatases shown by D. H. O'Connor, to be determinant of LTP and LTD, respectively. Specific predictions for various plasticity protocols are given by coupling this description of discrete synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor ligand gated ion channel conductance changes to a model of postsynaptic membrane potential and associated intracellular calcium fluxes to yield the transition rates among the states. We then present various LTP and LTD induction protocols to the model system and report the resulting whole cell changes in AMPA conductance. We also examine the effect of our discrete state synaptic plasticity model on the synchronization of realistic oscillating neurons. We show that one-to-one synchronization is enhanced by the plasticity we discuss here and the presynaptic and postsynaptic oscillations are in phase. Synaptic strength saturates naturally in this model and does not require artificial upper or lower cutoffs, in contrast to earlier models of plasticity.

Depressed Responses of Facilitatory Synapses

We show that when temporal summation takes place, depression of postsynaptic responses may ensue when the underlying synaptic conductance change is constant or even facilitatory. We term this phenomenon "apparent depression." Such apparent depression is most notable for slow synaptic conductance changes, for high frequency, and when the synapse is located at distal dendritic sites. We show that, when temporal summation ensues, the erroneous estimation of short-term synaptic plasticity arises partially from the conventional measurement of synaptic dynamics at postsynaptic potential peak time. This can be corrected when measuring overlapping synaptic responses at fixed intervals after stimulus time. Somatic voltage clamp also helps to partially correct for the apparent depression, but a good model of the neuron can do even better in providing a more accurate view of the underlying synaptic conductances.

Shunting Inhibition in Accessory Optic System Neurons

The interaction of excitatory and inhibitory inputs to the accessory optic system was studied with whole cell recordings in the turtle basal optic nucleus. Previous studies have shown that visual patterns, drifting in the same preferred direction, evoke excitatory and inhibitory postsynaptic events simultaneously. Analysis of the reversal potentials for these events and their pharmacological profile suggest that they are mediated by AMPA and GABA(A) receptors, respectively. Here, neurons were recorded to study nonlinear interaction between excitatory and inhibitory responses evoked by electrical microstimulation of the retina and pretectum, respectively. The responses to coincident activation of excitatory and inhibitory inputs exhibited membrane shunting in that the excitatory response amplitude, adjusted for changes in driving force, was attenuated during the onset of the inhibitory response. This nonlinear interaction was seen in many but not all stimulus pairings. In some cases, attenuation was followed by an augmentation of the excitatory response. For comparison, the size of the excitatory response was evaluated during a hyperpolarizing current pulse that directly modulated voltage-sensitive channels of a slow rectifying I(h) current. Injection of hyperpolarizing current did not cause the attenuation of the excitatory synaptic responses. We conclude that there is a nonlinear interaction between these excitatory and inhibitory synaptic currents that is not due to hyperpolarization itself, but probably is a result of their own synaptic conductance changes, i.e., shunting. Since these events are evoked by identical visual stimuli, this interaction may play a role in visual processing.

Determination of the location and magnitude of synaptic conductance changes in spinal motoneurons by impedance measurements.

The relation between impedance change and the location and magnitude of a tonic synaptic conductance was examined in compartmental motoneuron models based on previously published data. The dependency of motoneuron impedance on system time constant (tau), electrotonic length (L), and dendritic-to-somatic conductance ratio (rho) was examined, showing that the relation between impedance phase and rho differed markedly between models with uniform and nonuniform membrane resistivity. Dendritic synaptic conductances decreased impedance magnitude at low frequencies; at higher frequencies, impedance magnitude increased. The frequency at which the change in impedance magnitude reversed from a decrease to an increase-the reversal frequency, F(r)-was a good estimator of electrotonic synaptic location. A measure of the average normalized impedance change at frequencies less than F(r), cuDeltaZ, estimated relative synaptic conductance. F(r) and cuDeltaZ provided useful estimates of synaptic location and conductance in models with nonuniform (step, sigmoidal) and uniform membrane resistivity. F(r) also provided good estimates of spatial synaptic location on the equivalent cable in both step and sigmoidal models. Variability in relations between F(r), cuDeltaZ, and conductance location and magnitude between neurons was reduced by normalization with rho and tau. The effects on F(r) and cuDeltaZ of noise in experimental recordings, different synaptic distributions, and voltage-dependent conductances were also assessed. This study indicates that location and conductance of tonic dendritic conductances can be estimated from F(r), cuDeltaZ, and basic electrotonic motoneuron parameters with the exercise of suitable precautions.

Contribution of NMDA receptor channels to the expression of LTP in the hippocampal dentate gyrus.

The role of glutamatergic NMDA receptor channels (NMDARs) in the induction of long-term potentiation (LTP) has been well established. In contrast, whether or not NMDARs contribute to the expression of LTP has been an issue of debate. In this study, we investigated the contribution of NMDARs to LTP expression in the hippocampal dentate gyrus (DG) by stimulating perforant path afferents with short bursts of pulses delivered at a moderate frequency (40 Hz), instead of using the traditional protocol of a single stimulus at a low frequency (<0.1 Hz). The synaptic summation provided by the "burst" protocol enabled us to measure the NMDAR-mediated component of synaptic responses (NMDA component), defined as the NMDAR antagonist D-2-amino-5-phosphonovalerate (APV2+)-sensitive component, in the presence of physiological concentrations of Mg (1 mM). Intracellular recordings were obtained from DG granule cells of rabbit hippocampal slices, and excitatory postsynaptic potentials (EPSPs) were measured in terms of the integrated area of their profiles. At 40 Hz, frequency facilitation of the evoked EPSPs was observed. The NMDA component gradually increased during the five-pulse train and frequency facilitation was significantly reduced after the application of APV. We tested the hypothesis that NMDARs undergo potentiation in LTP by comparing the NMDA/non-NMDA ratio of the synaptic responses in control and LTP groups. An increase in the ratio was observed in the LTP group, strongly suggesting potentiation of NMDARs. To infer changes in conductance at individual synapses based on EPSPs recorded at the soma, we constructed a compartmental model of a morphologically reconstructed DG granule cell. The effect on the NMDA/non-NMDA ratio of changes in AMPA and NMDA component synaptic conductance, and of differences in the distribution of activated synapses, was studied with computer simulations. The results confirmed that NMDARs are potentiated after the induction of LTP and contribute significantly to the expression of potentiation under physiological conditions.