Time Course Of Synaptic Currents Research Articles

Synaptic variance and action potential firing of cerebellar output neurons during motor learning in larval zebrafish

The cerebellum regulates both reflexive and acquired movements. Here, by recording voltage-clamped synaptic currents and spiking in cerebellar output (eurydendroid) neurons in immobilized larval zebrafish, we investigated synaptic integration during reflexive movements and throughout associative motor learning. Spiking coincides with the onset of reflexive fictive swimming but precedes learned swimming, suggesting that eurydendroid signals may facilitate the initiation of acquired movements. Although firing rates increase during swimming, mean synaptic inhibition greatly exceeds mean excitation, indicating that learned responses cannot result solely from changes in synaptic weight or upstream excitability that favor excitation. Estimates of spike threshold crossings based on measurements of intrinsic properties and the time course of synaptic currents demonstrate that noisy excitation can transiently outweigh noisy inhibition enough to increase firing rates at swimming onset. Thus, the millisecond-scale variance of synaptic currents can regulate cerebellar output, and the emergence of learned cerebellar behaviors may involve a time-based code.

Shaping Neural Circuits by High Order Synaptic Interactions.

Spike timing dependent plasticity (STDP) is believed to play an important role in shaping the structure of neural circuits. Here we show that STDP generates effective interactions between synapses of different neurons, which were neglected in previous theoretical treatments, and can be described as a sum over contributions from structural motifs. These interactions can have a pivotal influence on the connectivity patterns that emerge under the influence of STDP. In particular, we consider two highly ordered forms of structure: wide synfire chains, in which groups of neurons project to each other sequentially, and self connected assemblies. We show that high order synaptic interactions can enable the formation of both structures, depending on the form of the STDP function and the time course of synaptic currents. Furthermore, within a certain regime of biophysical parameters, emergence of the ordered connectivity occurs robustly and autonomously in a stochastic network of spiking neurons, without a need to expose the neural network to structured inputs during learning.

Inferring network model from local field potentials

Experimental study of neural information processing requires simultaneous sampling of the activity of multiple cells over the network. One of the promising approaches relies on monitoring local field potentials (LFPs) by multi-electrode arrays that can span large brain regions (see Figure 1A,B). LFPs may contain firing activity of different cells and, more importantly, they capture synaptic activity produced by principal cells. Thus LFPs enclose extremely rich information on how principal cells integrate converging inputs coming from multiple neuronal populations. However, since synaptic currents mix in the extracellular volume, LFPs have complex spatiotemporal structure making them hard to be exploited. Recently we proposed a biophysical framework to identify and separate LFPs into so-called LFP-generators [1]. Here we discuss how this technique can be used to identify spatial characteristics and temporal patterns of main LFP-generators actuating in the rat hippocampus. The electrical activity of each generator is defined by the spatial distribution of synaptic terminals and the time course of synaptic currents initiated by spike trains sent by the corresponding presynaptic population. Remarkably some recognized pathways do not contribute notably to LFPs [2]. We localized synaptic inputs with subcellular accuracy and reconstructed time courses of main LFP-generators up to millisecond time scales. We were able to readout in parallel the pathway-specific presynaptic activity of projection cells in the entorhinal cortex and pyramidal cells in the ipsilateral and contralateral CA3. We also provide results on spatial extension of the generators. Then we use a computational multi-neuronal model (see Figure ​Figure1C)1C) that scales up single cell electrogenesis driven by several synaptic inputs to realistic aggregate LFPs. This approach relies on the fixed but distinct locations of synaptic inputs from different presynaptic populations obtained experimentally. We show that this approach reliably reproduces ongoing LFPs in the hippocampus (see Figure ​Figure1D).1D). Then simulated LFPs can be used for studying relationships between phases of LFP-generators and spike trains fired by presynaptic neurons (see Figure ​Figure1E).1E). We show that the phase-spike relations provide information on spatial location of axon terminals in contrast to extended opinion on phase spike locking. Figure 1 Inferring network dynamics from LFPs. A. Sketch of experimental setup. Multi-electrode spans CA1-CA3 region of the rat hippocampus. B. Experimental spontaneous LFPs. C. local circuit included in the model. D. Simulated LFPs. E. Phase-spike relations.

Extracellular Protons Reduce Quantal Content and Prolong Synaptic Currents at the Drosophila Larval Neuromuscular Junction

: Fluctuations in extracellular pH occur in the nervous system in response to a number of physiological and pathological processes, such as ischemia, hypercapnea, and high-frequency activity. Using the Drosophila larval neuromuscular junction, the author has examined acute effects of low and high pH on excitability and synaptic transmission. Acidification rapidly and reversibly reduces the size of electrically evoked excitatory junctional currents (EJCs) in a concentration-dependent manner, with transmission nearly abolished at pH 5.0. Conversely, raising pH to 7.8 increases EJC amplitude significantly. Further elevation to pH 8.5 causes an initial increase in amplitude, followed by profound, long-lasting depression of the synapse. Amplitudes of spontaneous miniature EJCs (mEJCs) are modestly, but significantly reduced at pH 5.0. It is therefore the number of quanta released per action potential, rather than the size of individual quanta, that is most strongly affected. Decay times of both EJCs and mEJCs are dramatically lengthened at low pH, suggesting that glutamate remains in the synaptic cleft for much longer than normal. Presynaptic excitability is also reduced, as indicated by increased latency between nerve shock and EJC onset. The response to low pH was not altered by mutations in genes encoding Transient Receptor Potential, Mucolipin subfamily (TRPML) and Slowpoke ion channels, which had previously been implicated as possible targets of extracellular protons. The author concludes that extracellular protons have strong effects on the release of glutamate and the time course of synaptic currents. These phenotypes can be exploited to study the mechanisms of acid-mediated changes in neuronal function, and to pursue the way in which pH modulates synaptic function in normal and pathophysiological conditions.

Impact of Synaptic Neurotransmitter Concentration Time Course on the Kinetics and Pharmacological Modulation of Inhibitory Synaptic Currents

The time course of synaptic currents is a crucial determinant of rapid signaling between neurons. Traditionally, the mechanisms underlying the shape of synaptic signals are classified as pre- and post-synaptic. Over the last two decades, an extensive body of evidence indicated that synaptic signals are critically shaped by the neurotransmitter time course which encompasses several phenomena including pre- and post-synaptic ones. The agonist transient depends on neurotransmitter release mechanisms, diffusion within the synaptic cleft, spill-over to the extra-synaptic space, uptake, and binding to post-synaptic receptors. Most estimates indicate that the neurotransmitter transient is very brief, lasting between one hundred up to several hundreds of microseconds, implying that post-synaptic activation is characterized by a high degree of non-equilibrium. Moreover, pharmacological studies provide evidence that the kinetics of agonist transient plays a crucial role in setting the susceptibility of synaptic currents to modulation by a variety of compounds of physiological or clinical relevance. More recently, the role of the neurotransmitter time course has been emphasized by studies carried out on brain slice models that revealed a striking, cell-dependent variability of synaptic agonist waveforms ranging from rapid pulses to slow volume transmission. In the present paper we review the advances on studies addressing the impact of synaptic neurotransmitter transient on kinetics and pharmacological modulation of synaptic currents at inhibitory synapses.

Parallel readout of pathway-specific inputs to laminated brain structures

Local field potentials (LFPs) capture the electrical activity produced by principal cells during integration of converging synaptic inputs from multiple neuronal populations. However, since synaptic currents mix in the extracellular volume, LFPs have complex spatiotemporal structure, making them hard to exploit. Here we propose a biophysical framework to identify and separate LFP-generators. First we use a computational multineuronal model that scales up single cell electrogenesis driven by several synaptic inputs to realistic aggregate LFPs. This approach relies on the fixed but distinct locations of synaptic inputs from different presynaptic populations targeting a laminated brain structure. Thus the LFPs are contributed by several pathway-specific LFP-generators, whose electrical activity is defined by the spatial distribution of synaptic terminals and the time course of synaptic currents initiated in target cells by the corresponding presynaptic population. Then we explore the efficacy of independent component analysis to blindly separate converging sources and reconstruct pathway-specific LFP-generators. This approach can optimally locate synaptic inputs with subcellular accuracy while the reconstructed time course of pathway-specific LFP-generators is reliable in the millisecond scale. We also describe few cases where the non-linear intracellular interaction of strongly overlapping LFP-generators may lead to a significant cross-contamination and the appearance of derivative generators. We show that the approach reliably disentangle ongoing LFPs in the hippocampus into contribution of several LFP-generators. We were able to readout in parallel the pathway-specific presynaptic activity of projection cells in the entorhinal cortex and pyramidal cells in the ipsilateral and contralateral CA3. Thus we provide formal mathematical and experimental support for parallel readout of the activity of converging presynaptic populations in working neuronal circuits from common LFPs.

Kissing or Fused Since Some Time

Kissing or Fused Since Some Time

Dynamics of Fast and Slow Inhibition from Cerebellar Golgi Cells Allow Flexible Control of Synaptic Integration

Throughout the brain, multiple interneuron types influence distinct aspects of synaptic processing. Interneuron diversity can thereby promote differential firing from neurons receiving common excitation. In contrast, Golgi cells are the sole interneurons regulating granule cell spiking evoked by mossy fibers, thereby gating inputs to the cerebellar cortex. Here, we examine how this single interneuron class modifies activity in its targets. We find that GABA(A)-mediated transmission at unitary Golgi cell --> granule cell synapses consists of varying contributions of fast synaptic currents and sustained inhibition. Fast IPSCs depress and slow IPSCs gradually build during high-frequency Golgi cell activity. Consequently, fast and slow inhibition differentially influence granule cell spike timing during persistent mossy fiber input. Furthermore, slow inhibition reduces the gain of the mossy fiber --> granule cell input-output curve, while fast inhibition increases the threshold. Thus, a lack of interneuron diversity need not prevent flexible inhibitory control of synaptic processing.

Neuroligin-2 accelerates GABAergic synapse maturation in cerebellar granule cells

Neuroligins (NLGs) are postsynaptic cell adhesion molecules that are thought to function in synaptogenesis. To investigate the role of NLGs on synaptic transmission once the synapse is formed, we transfected neuroligin-2 (NLG-2) in cultured mouse cerebellar granule cells (CGCs), and recorded GABA A (γ-aminobutyric acid) receptor mediated miniature postsynaptic currents (mIPSCs). NLG-2 transfected cells had mIPSCs with faster decay than matching GFP expressing controls at young culture ages (days in vitro, DIV7–8). Down-regulation of NLG-2 by the isoform specific shRNA-NLG-2 resulted in an opposite effect. We and others have shown that the switch of α subunits of GABA ARs from α2/3 to α1 underlies developmental speeding of the IPSC decay in various CNS regions, including the cerebellum. To assess whether the reduced decay time of mIPSCs by NLG-2 is due to the recruitment of more α1 containing GABA ARs at the synapses, we examined the prolongation of current decay by the Zolpidem, which has been shown to preferentially enhance the activity of α1 subunit-containing GABA channel. The application of Zolpidem resulted in a significantly greater prolongation kinetics of synaptic currents in NLG-2 over-expressing cells than control cells, suggesting that NLG-2 over-expression accelerates synapse maturation by promoting incorporation of the α1 subunit-containing GABA ARs at postsynaptic sites in immature cells. In addition, the effect of NLG-2 on the speeding of decay time course of synaptic currents was abolished when we used CGC cultures from α1−/− mice. Lastly, to exclude the possibility that the fast decay of mIPSCs induced by NLG-2 could be also due to the impacts of NLG-2 on the GABA transient in synaptic cleft, we measured the sensitivity of mIPSCs to the fast-off competitive antagonists TPMPA. We found that TPMPA similarly inhibits mIPSCs in control and NLG-2 over-expressing CGCs both at young age (DIV8) and old age (DIV14) of cultures. However, we confirm our previous finding of a greater inhibition of mIPSCs in young (DIV8) than more mature (DIV14) cultures. Together, our results suggest that NLG-2 does not alter uniquantal GABA release, and the fast decay of mIPSC induced by NLG-2 is due to the differential expression of postsynaptic GABA A receptor subtypes. Taken all together, we propose that NLG-2 plays important functional role in inhibitory synapse development and maturation.

Fenestration of the calyx of held occurs sequentially along the tonotopic axis, is influenced by afferent activity, and facilitates glutamate clearance

The calyx of Held is a type of giant glutamatergic presynaptic terminal in the mammalian auditory brainstem that transmits afferent information from the cochlear nucleus to the medial nucleus of the trapezoid body (MNTB). It participates in sound localization, a process that requires very high temporal precision. Consistent with its functional role, the calyx shows a number of specializations for temporal fidelity, one of them being the giant terminal itself with its many release sites. During the first 3 weeks of postnatal development, the calyx transforms from a spoon-shaped, closed morphology to a highly fenestrated open structure. Calyces in Mongolian gerbils (Meriones unguiculatus) were labeled via injection of fluorescent tracers and their morphology was reconstructed at various timepoints during early postnatal development. We show that the fenestration process does not occur simultaneously in all calyces. Calyces transmitting high-frequency sound information fenestrate significantly earlier than those transmitting low-frequency information, such that a temporary developmental gradient along the tonotopic axis is established around the time of hearing onset. Animals that were deprived of afferent activity before hearing onset, either via cochlear removal or administration of ototoxic drugs, do not show this developmental gradient. Glial processes containing glutamate transporters occupy the newly created windows in the calyx and thus could augment the fast clearance of neurotransmitter. The physiological consequences of this faster clearance include a faster decay time course of synaptic currents as well as a lower amount of residual current accumulating during the processing of repeated activity such as stimulus trains.

Electrophysiological description of mechanisms determining synaptic transmission and its modulation.

Signal integration in neurons is a complex process that depends on e.g. the kinetics of synaptic currents, distribution of synaptic connections as well as passive and excitatory membrane properties. The time course of synaptic currents is largely determined by the kinetics of the postsynaptic receptors and the time course of synaptic neurotransmitter concentration. The analysis of current responses to rapid agonist applications provides the means to study the ligand-gated receptor gating but experimentally based estimation of neurotransmitter transient at central synapses was an important challenge during the last decade. Both theoretical as well as experimentally based approaches indicated that synaptic agonist transient is very brief, implying that the activation of postsynaptic receptors occurs in conditions of extreme non-equilibrium. Such a dynamic pattern of activation of postsynaptic receptors has a crucial impact not only on the kinetics of synaptic currents but also on their susceptibility to pharmacological modulation.

Different Roles for AMPA and NMDA Receptors in Transmission at the Immature Retinogeniculate Synapse

The relay of information at the retinogeniculate synapse, the connection between retina and visual thalamus, begins days before eye opening and is thought to play an important role in the maturation of neural circuits in the thalamus and visual cortex. Remarkably, during this period of development, the retinogeniculate synapse is immature, with single retinal ganglion cell inputs evoking an average peak excitatory postsynaptic current (EPSC) of only about 40 pA compared with 800 pA in mature synapses. Yet, at the mature synapse, EPSCs >400 pA are needed to drive relay neuron firing. This raises the question of how small-amplitude EPSCs can drive transmission at the immature retinogeniculate synapse. Here we find that several features of the immature synapse, compared with the mature synapse, contribute to synaptic transmission. First, although the peak amplitude of EPSC is small, the decay time course of both alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) currents is significantly slower. The prolonged time course of NMDAR currents is a result of the presence of both NR2B and NR2C/D subunits. In addition, the extended presence of neurotransmitter released prolongs the synaptic current time course. Second, reduced sensitivity to magnesium block results in significantly greater synaptic charge transfer through NMDAR. Third, AMPAR currents contribute to the spike latency, but not to temporal precision, at the immature synapse. Furthermore, intrinsic excitability is greater. These properties enable immature synapses with predominantly NMDARs and little or no AMPARs to contribute to the relay of information from retina to visual cortex.

Lysosomal Dysfunction Produces Distinct Alterations in Synaptic α-Amino-3-Hydroxy-5-Methylisoxazolepropionic Acid and N-Methyl-D-Aspartate Receptor Currents in Hippocampus

The early processes that lead to synaptic dysfunction during aging are not clearly understood. Dysregulation of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors may cause age-related cognitive decline. Using hippocampal slice cultures exhibiting lysosomal dysfunction, an early marker of brain aging that is linked to protein accumulation, we identified alterations to AMPA and NMDA receptor-mediated synaptic currents. The miniature and spontaneous excitatory postsynaptic currents that were examined after 3, 6, and 9 days of lysosomal disruption showed progressive changes in amplitude, frequency, and rise and decay kinetics. To investigate whether modifications in specific channel properties of single synaptic receptors contributed to changes in the amplitude and time course of synaptic currents, we examined the single channel properties of synaptic AMPA and NMDA receptors. The channel open probability and the mean open times showed decreases in both receptor populations, whereas the closed times were increased without any change in the channel conductance. The Western blot analysis revealed a progressive decline in synaptic markers including glutamate receptor subunits. These results indicate that lysosomal dysfunction leads to progressive functional perturbation of AMPA and NMDA receptors in this slice model of protein accumulation, suggesting that age-related cognitive decline could result from altered glutamate receptor function before reductions in synaptic density.

TARP Subtypes Differentially and Dose-Dependently Control Synaptic AMPA Receptor Gating

A family of transmembrane AMPA receptor regulatory proteins (TARPs) profoundly affects the trafficking and gating of AMPA receptors (AMPARs). Although TARP subtypes are differentially expressed throughout the CNS, it is unclear whether this imparts functional diversity to AMPARs in distinct neuronal populations. Here, we examine the effects of each TARP subtype on the kinetics of AMPAR gating in heterologous cells and in neurons. We report a striking heterogeneity in the effects of TARP subtypes on AMPAR deactivation and desensitization, which we demonstrate controls the time course of synaptic transmission. In addition, we find that some TARP subtypes dramatically slow AMPAR activation kinetics. Synaptic AMPAR kinetics also depend on TARP expression level, suggesting a variable TARP/AMPAR stoichiometry. Analysis of quantal synaptic transmission in a TARP gamma-4 knockout (KO) mouse corroborates our expression data and demonstrates that TARP subtype-specific gating of AMPARs contributes to the kinetics of native AMPARs at central synapses.

Activation of heteroliganded mouse muscle nicotinic receptors

The activation of the mouse muscle-type nicotinic acetylcholine receptor was studied in the presence of carbachol, and in the simultaneous presence of carbachol and choline. The channel currents were recorded under steady-state conditions using cell-attached single-channel patch clamp, and during transient exposures to the agonists using a piezo-driven fast application system. The presence of choline resulted in inhibition of currents elicited by carbachol. The inhibitory effect of choline manifested as a reduction in the effective opening rate (increase in the mean intracluster closed time duration) in single-channel recordings. In the fast application experiments, the peak current amplitude was reduced and the current rise time increased when choline was co-applied with carbachol. The data were analysed according to a model in which receptor interactions with carbachol and choline resulted in three types of ligation: receptors occupied by two carbachol molecules, receptors occupied by two choline molecules, and receptors in which one agonist binding site was occupied by carbachol and the other by choline, i.e. heteroliganded receptors. All three agonist-bound receptor populations could open albeit with different efficacies. The affinity of the resting receptor to choline was estimated to be 1-2 mm, and heteroliganded receptors opened with an opening rate constant of approximately 3000 s(-1). The results of the analysis suggest that the presence of choline in the neuromuscular junction in vivo has little effect on the time course of synaptic currents. Nevertheless, the contribution of heteroliganded receptors should be taken into consideration when the receptor is exposed simultaneously to two or more agonists.

Developmental Changes of GABA Synaptic Transient in Cerebellar Granule Cells

The time course of synaptic currents is largely determined by the microscopic gating of the postsynaptic receptors and the temporal profile of the synaptic neurotransmitter concentration. Although several lines of evidence indicate that developmental changes of GABAergic synaptic current time course are clearly correlated with a switch in postsynaptic receptors, much less is known about the modification of GABA release during development. To address this issue, we studied the sensitivity of miniature inhibitory postsynaptic currents (mIPSCs) to a quickly dissociating competitive antagonist, 1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA), in neurons cultured for 6 to 8 days in vitro (DIV) ("young") and for 12 to 14 DIV ("old"). mIPSCs recorded in young neurons were significantly more resistant to the block by TPMPA. This observation was interpreted as a consequence of a more efficient displacement of TPMPA from GABA(A) receptors caused by a stronger GABA release in young neurons. The change in mIPSC sensitivity to TPMPA during development was not affected by the deletion of alpha(1) subunit, supporting its presynaptic origin. The effects of a second quickly dissociating antagonist, SR-95103 [2-(carboxy-3'-propyl)-3-amino-4-methyl-6-phenylpyridazinium chloride], on young, old, and alpha(1) -/- neurons were qualitatively the same as those obtained with TPMPA. Moreover, the analysis of current responses to ultrafast GABA applications showed that the unbinding rates of TPMPA in DIV 6 to 8 and in DIV 12 to 14 neurons are not significantly different, ruling out the postsynaptic mechanism of differential TPMPA action. Thus, we provide evidence that presynaptic GABA uniquantal release is developmentally regulated.

Direct Effects of Calmodulin on NMDA Receptor Single-Channel Gating in Rat Hippocampal Granule Cells

NMDA receptors are glutamate-sensitive ion channel receptors that mediate excitatory synaptic transmission and are widely implicated in synaptic plasticity and integration of synaptic activity in the CNS. This is in part attributable to the high calcium permeability of the ion channel, which allows receptor activation to influence the intracellular calcium concentration and also the slow time course of NMDA receptor-mediated synaptic currents. NMDA receptor activity is also regulated by the intracellular calcium concentration through activation of various calcium-dependent proteins, including calmodulin, calcineurin, protein kinase C, and alpha-actinin-2. Here, we have shown that calmodulin reduces the duration of native NMDA receptor single-channel openings from 3.5 +/- 0.6 msec to 1.71 +/- 0.2 msec in agreement with previous studies on recombinant NMDA receptors (Ehlers et al., 1996). NMDA receptor single-channel amplitudes and shut times were not affected. However, calmodulin reduced the duration of groups of channel openings called superclusters, which determine the slow time course of synaptic currents, from 121 +/- 25.4 msec to 60.4 +/- 11.6 msec. In addition, total open time, number of channel openings, and charge transfer per supercluster were all reduced by calmodulin. A 68% decrease in charge transfer per supercluster suggests that calmodulin activation will significantly reduce calcium influx during synaptic transmission. These results suggest that calmodulin-dependent inhibition of NMDA receptors will reduce the amplitude and time course of excitatory synaptic currents and thus affect synaptic plasticity and integration of synaptic activity in the CNS.

Activity-Dependent Change in AMPA Receptor Properties in Cerebellar Stellate Cells

High-frequency synaptic stimulation is thought to cause a rapid and lasting change in the expression of GluR2 subunit-containing AMPA receptors (AMPARs) at synapses in cerebellar stellate cells. We examined whether spontaneous synaptic activity affects the expression of GluR2-containing synaptic AMPARs and whether the change in AMPAR subtypes alters their Ca2+permeability and kinetic properties. We used intracellular spermine, which blocks GluR2-lacking receptors at depolarized potentials, to distinguish the presence of GluR2. In most cells, the spontaneous EPSC frequency was low, and evoked EPSCs displayed inwardly rectifyingI–Vrelationships, indicative of the presence of GluR2-lacking AMPARs. However, in cells that displayed a higher rate of spontaneous synaptic activity, EPSCs gave linearI–Vplots, suggesting the presence of GluR2-containingAMPARs. This is consistent with the idea that spontaneous synaptic activity increased the expression of GluR2-containing AMPARs at synapses. The Ca2+permeability of AMPARs that gave inwardly rectifying currents in outside-out patches from TTX-treated cells was six times higher than in control cells that gave linear or outwardly rectifyingI–Vplots. However, increased spontaneous synaptic activity did not significantly alter the EPSC decay time. Furthermore, the decay time course ofEPSCs mediated by GluR2-containing receptors was not different from that mediated by a mixed population of receptors at the same synapse. Our results suggest that the level of spontaneous synaptic activity can determine the subunit composition of postsynaptic receptors at this synapse. The activity-induced expression of GluR2-containing receptors significantly reduced the Ca2+permeability of AMPARs in stellate cells but did not slow the decay time course of synaptic currents.

Activity-dependent change in AMPA receptor properties in cerebellar stellate cells.

High-frequency synaptic stimulation is thought to cause a rapid and lasting change in the expression of GluR2 subunit-containing AMPA receptors (AMPARs) at synapses in cerebellar stellate cells. We examined whether spontaneous synaptic activity affects the expression of GluR2-containing synaptic AMPARs and whether the change in AMPAR subtypes alters their Ca(2+) permeability and kinetic properties. We used intracellular spermine, which blocks GluR2-lacking receptors at depolarized potentials, to distinguish the presence of GluR2. In most cells, the spontaneous EPSC frequency was low, and evoked EPSCs displayed inwardly rectifying I-V relationships, indicative of the presence of GluR2-lacking AMPARs. However, in cells that displayed a higher rate of spontaneous synaptic activity, EPSCs gave linear I-V plots, suggesting the presence of GluR2-containingAMPARs. This is consistent with the idea that spontaneous synaptic activity increased the expression of GluR2-containing AMPARs at synapses. The Ca(2+) permeability of AMPARs that gave inwardly rectifying currents in outside-out patches from TTX-treated cells was six times higher than in control cells that gave linear or outwardly rectifying I-V plots. However, increased spontaneous synaptic activity did not significantly alter the EPSC decay time. Furthermore, the decay time course ofEPSCs mediated by GluR2-containing receptors was not different from that mediated by a mixed population of receptors at the same synapse. Our results suggest that the level of spontaneous synaptic activity can determine the subunit composition of postsynaptic receptors at this synapse. The activity-induced expression of GluR2-containing receptors significantly reduced the Ca(2+) permeability of AMPARs in stellate cells but did not slow the decay time course of synaptic currents.

Influence of Temporal Correlation of Synaptic Input on the Rate and Variability of Firing in Neurons

The spike trains that transmit information between neurons are stochastic. We used the theory of random point processes and simulation methods to investigate the influence of temporal correlation of synaptic input current on firing statistics. The theory accounts for two sources for temporal correlation: synchrony between spikes in presynaptic input trains and the unitary synaptic current time course. Simulations show that slow temporal correlation of synaptic input leads to high variability in firing. In a leaky integrate-and-fire neuron model with spike afterhyperpolarization the theory accurately predicts the firing rate when the spike threshold is higher than two standard deviations of the membrane potential fluctuations. For lower thresholds the spike afterhyperpolarization reduces the firing rate below the theory’s predicted level when the synaptic correlation decays rapidly. If the synaptic correlation decays slower than the spike afterhyperpolarization, spike bursts can occur during single broad peaks of input fluctuations, increasing the firing rate over the prediction. Spike bursts lead to a coefficient of variation for the interspike intervals that can exceed one, suggesting an explanation of high coefficient of variation for interspike intervals observed in vivo.