Peak Amplitude Of Excitatory Postsynaptic Potentials Research Articles

Feed-forward recruitment of electrical synapses enhances synchronous spiking in the mouse cerebellar cortex.

In the cerebellar cortex, molecular layer interneurons use chemical and electrical synapses to form subnetworks that fine-tune the spiking output of the cerebellum. Although electrical synapses can entrain activity within neuronal assemblies, their role in feed-forward circuits is less well explored. By combining whole-cell patch-clamp and 2-photon laser scanning microscopy of basket cells (BCs), we found that classical excitatory postsynaptic currents (EPSCs) are followed by GABAA receptor-independent outward currents, reflecting the hyperpolarization component of spikelets (a synapse-evoked action potential passively propagating from electrically coupled neighbors). FF recruitment of the spikelet-mediated inhibition curtails the integration time window of concomitant excitatory postsynaptic potentials (EPSPs) and dampens their temporal integration. In contrast with GABAergic-mediated feed-forward inhibition, the depolarizing component of spikelets transiently increases the peak amplitude of EPSPs, and thus postsynaptic spiking probability. Therefore, spikelet transmission can propagate within the BC network to generate synchronous inhibition of Purkinje cells, which can entrain cerebellar output for driving temporally precise behaviors.

Diffusion-Based Model for Synaptic Molecular Communication Channel.

Computational methods have been extensively used to understand the underlying dynamics of molecular communication methods employed by nature. One very effective and popular approach is to utilize a Monte Carlo simulation. Although it is very reliable, this method can have a very high computational cost, which in some cases renders the simulation impractical. Therefore, in this paper, for the special case of an excitatory synaptic molecular communication channel, we present a novel mathematical model for the diffusion and binding of neurotransmitters that takes into account the effects of synaptic geometry in 3-D space and re-absorption of neurotransmitters by the transmitting neuron. Based on this model we develop a fast deterministic algorithm, which calculates expected value of the output of this channel, namely, the amplitude of excitatory postsynaptic potential (EPSP), for given synaptic parameters. We validate our algorithm by a Monte Carlo simulation, which shows total agreement between the results of the two methods. Finally, we utilize our model to quantify the effects of variation in synaptic parameters, such as position of release site, receptor density, size of postsynaptic density, diffusion coefficient, uptake probability, and number of neurotransmitters in a vesicle, on maximum number of bound receptors that directly affect the peak amplitude of EPSP.

Dual effect of GABA on descending monosynaptic excitatory postsynaptic potential in frog lumbar motoneurons

Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulating ipsilateral ventrolateral column (VLC) in the thoracic section were recorded in lumbar motoneurons within the isolated spinal cord of the frog Rana ridibunda. Bath application of the selective GABA B receptor agonist (−)-baclofen (0.05 mM) caused a reduction in the peak amplitude of VLC EPSP. Baclofen did not cause any consistent change in the membrane potential or in the EPSP waveform within frog motoneurones. The selective GABA B receptor antagonist saclofen (0.1 mM) completely blocked the effect of (−)-baclofen on VLC EPSP. A decrease in VLC EPSP peak amplitude was also observed during GABA (0.5 mM) application. Unlike (−)-baclofen, inhibition of VLC EPSP induced by GABA was accompanied by a shortening of the EPSP time course and a reduction in membrane input resistance within lumbar motoneurons. The decrease in VLC EPSP peak amplitude induced by (−)-baclofen and GABA was accompanied by an increase in the paired-pulse facilitation. These data provide evidence for a dual pre- and postsynaptic GABAergic inhibition of the VLC monosynaptic EPSP in lumbar motoneurons within the frog spinal cord.

Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering.

Distal versus proximal inhibitory shaping of feedback excitation in the electrosensory lateral line lobe: implications for sensory filtering. J. Neurophysiol. 80: 3214-3232, 1998. The inhibition controlling the indirect descending feedback (parallel fibers originating from cerebellar granule cells in the eminentia posterior pars granularis) to electrosensory lateral line lobe (ELL) pyramidal cells was studied using intracellular recording techniques in vitro. Parallel fibers (PF) contact stellate cells and dendrites of ventral molecular layer (VML) GABAergic interneurons. Stellate cells provide local input to pyramidal cell distal dendrites, whereas VML cells contact their somata and proximal dendrites. Single-pulse stimulation of PF evoked graded excitatory postsynaptic potentials (EPSPs) that were blocked by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl--aspartate (NMDA) antagonists. The EPSPs peaked at 6.4 +/- 1.8 ms (mean +/- SE; n = 11) but took >50 ms to decay completely. Tetanic stimulation (100 ms, 100 Hz) produced a depolarizing wave with individual EPSPs superimposed. The absolute amplitude of the individual EPSPs decreased during the train. Spike rates, established by injected current, mostly were increased, but in some cells were decreased, by tetanic stimulation. Global application of a gamma-aminobutyric acid-A (GABAA) antagonist to the recorded cell's soma and apical dendritic region increased the EPSP peak and decay phase amplitudes. Tetanic stimulation always increased current-evoked spike rates after GABAA blockade during, and for several hundred milliseconds after, the stimulus. Application of a GABAB antagonist did not have any significant effects on the PF-evoked response. This, and the lack of any long hyperpolarizing inhibitory postsynaptic potentials, suggests that VML and stellate cell inhibition does not involve GABAB receptors. Focal GABAA antagonist applications to the dorsal molecular layer (DML) and pyramidal cell layer (PCL) had contrasting effects on PF-evoked EPSPs. DML GABAA blockade significantly increased the EPSP peak amplitude but not the decay phase of the EPSP, whereas PCL GABAA-blockade significantly increased the decay phase, but not the EPSP peak, amplitude. The order of antagonist application did not affect the outcome. On the basis of the known circuitry of the ELL, we conclude that the distal inhibition originated from GABAergic molecular layer stellate cells and the proximal inhibition originated from GABAergic cells of the ventral molecular layer (VML cells). Computer modeling of distal and proximal inhibition suggests that intrinsic differences in IPSP dynamics between the distal and proximal sites may be amplified by voltage-dependent NMDA receptor and persistent sodium currents. We propose that the different time courses of stellate cell and VML cell inhibition allows them to act as low- and high-pass filters respectively on indirect descending feedback to ELL pyramidal cells.

Dual-component excitatory amino acid-mediated responses in trigeminal motoneurons and their modulation by serotonin in vitro.

1. Intracellular recordings were made from guinea pig trigeminal motoneurons in brain stem slices. Monosynaptic excitatory postsynaptic potentials (EPSPs) were evoked in trigeminal motoneurons by focal stimulation of the mesencephalic nucleus of V (Mes V), a region containing cell bodies of primary afferent fibers of jaw muscle spindle and periodontal receptor origin. 2. The presence of N-methyl-D,L-aspartate (NMDA) and non-NMDA excitatory amino acid receptors (EAAs) was determined by iontophoretic application of NMDA and (+/-)-alpha-amino-3-hydroxy methylisoxazole-4-propionic acid (AMPA) from multi-barreled micropipettes. Application of either agonist in normal Mg(2+)-containing extracellular solutions produced a membrane depolarization or inward current from resting potential in current-or voltage-clamp modes, respectively. However, the voltage and current responses to NMDA and AMPA differed in their dependence on initial membrane potential. In voltage clamp between -70 and -50 mV, the peak current response to NMDA application increased whereas the response to AMPA application decreased as a function of holding potential. 3. Mes-V-induced synaptic potentials were examined for the presence of NMDA and non-NMDA components in extracellular solutions devoid of Mg2+. In the presence of DL-2-amino-5-phosphonopentanoic acid (30 microM), the peak amplitude and half-amplitude duration were decreased 52 and 36% (n = 2), respectively, compared with control. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10-15 microM), a specific non-NMDA antagonist, the mean decrease in evoked synaptic potential amplitude was 55% (n = 5), but the half-amplitude duration increased by a mean of 63% (n = 5). 4. The non-NMDA component of the evoked EPSP obtained in the presence of DL-2-amino-5-phosphonovaleric acid showed a linear decrease in peak amplitude as a function of holding potential. In contrast, the NMDA EPSP component obtained in the presence of CNQX increased in peak amplitude as a function of holding potential between -70 and -40 mV. The increase in EPSP peak amplitude was abolished by removal of Mg2+ from the extracellular media. 5. Bath application of serotonin (5-HT) (50-100 microM) increased the peak NMDA and non-NMDA EPSP components by 31% (n = 10) and 23% (n = 8), respectively, while producing a mean increase in half-amplitude duration of 67 and 88%, respectively. Concomitantly, 5-HT increased input resistance by approximately 40% and produced a membrane depolarization. 6. In the presence of tetrodotoxin, 5-HT enhanced both iontophoretic NMDA and AMPA voltage responses. In cells voltage clamped between -60 and -70 mV in Mg(2+)-free solutions, iontophoretic NMDA and AMPA peak currents were enhanced 27 and 32%, respectively, by 5-HT. 7. The enhancement of the iontophoretic NMDA and non-NMDA responses was mimicked by (+/-)-1-(2,5-dimethyoxy-4-iodophenyl)-2- aminopropane HCL and blocked by 3-[2-[4-(fluorobenzoyl)-1-piperdinyl]-2,4 (1H,3H)-quinazolinedione-tartrate and N'-[(8a)-1,6-dimethylergolin-8-yl]-N,N-dimethyl-sulfamide hydrochloride, suggesting 5-HT2 receptor involvement. 8. The results demonstrate that trigeminal motoneurons possess both NMDA and non-NMDA receptors that are activated during Mes-V-induced synaptic transmission. The data suggest that EAA-mediated responses in trigeminal motoneurons are substrates for modulation by 5-HT via changes in membrane resistance and modulation of the EAA-induced synaptic current.

Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice.

1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of < 10% after pairings suggested that H-7 partially blocked PSD and that, in turn, PSD involved protein kinases. 6. The means of induction and the specificity of those means suggest that the phenomenology of PSD is fundamentally different from that of long-term depression. PSD only occurs with pairings of trains of parallel fiber and climbing fiber stimulation; it occurs without the need for bicuculline; and it can overcome the blocking effects of aniracetam. 7. Nevertheless, the involvement of protein kinases and the potential role of calcium suggest that the mechanisms involved in the induction of PSD and long-term depression have a number of features in common. 8. Because of the pairing-specific nature of the long-term synaptic depression observed in these experiments, PSD provides a mechanism that may contribute to the role of the cerebellar cortex in classical conditioning.

Kappa-opioid receptor agonists modulate excitatory transmission in substantia gelatinosa neurons of the rat spinal cord

This study examined the effects of selective activation of kappa 1-opioid receptors on excitatory transmission in substantia gelatinosa (SG) using intracellular recordings from SG neurons in transverse slices of the young rat lumbar spinal cord. Monosynaptic and polysynaptic excitatory postsynaptic potentials (EPSPs) were evoked by orthodromic electrical stimulation of A delta or C primary afferent fibers in the dorsal root after blocking inhibitory inputs with bicuculline and strychnine, NMDA receptors with D-2-amino-5-phosphonovaleric acid and mu- and delta-opioid receptors with CTAP and ICI 174,864, respectively. Bath application of dynorphin A1-17 or U-69, 593 caused dual modulation of the peak amplitude of presumed monosynaptic AMPA receptor-mediated EPSPs, decreasing synaptic potentials at nanomolar concentrations in a majority of SG cells examined (dynorphin, 63%; U-69,593, 91%), and increasing EPSPs at micromolar concentrations. Only the inhibitory action of dynorphin A1-17 was consistently and completely blocked by norbinaltorphimine (nor-BNI). Since U-69,593 and nor-BNI are selective for the kappa 1-opioid receptors, the depression of EPSPs is likely to be mediated by the kappa1-opioid receptors. Under conditions of blockade of synaptic transmission with TTX and mu-and delta-opioid receptors, dynorphin A1-17 and U-69,593 hyperpolarize most of SG neurons and decrease their membrane input resistance, the finding suggesting that direct interaction of kappa-agonists with a postsynaptic receptor is likely explanation for the inhibition of EPSPs. However, in some SG cells, the inhibition of EPSPs appears to be of presynaptic origin since dynorphin A1-17 and U-69,593 did depress the EPSPs in the absence of changes in passive membrane properties. Rp-cAMPS, a membrane permeant potent competitive inhibitor of cAMP-activated protein kinase, prevented the depressant effect of dynorphin A 1-17. This finding suggested a possibility that dynorphin A1-17, acting through a decrease in intracellular cyclic AMP levels, can reduce the synaptic responses of SG neurons. These results provide the first electrophysiological demonstration that the activation of kappa 1-opioid receptors inhibits AMPA receptor-mediated primary afferent neurotransmission in the substantia gelatinosa of the young rat spinal cord. This effect may mediate the ability of kappa-receptor agonists to produce antinociception.

EPSPs in rat neocortical pyramidal neurones in vitro are prolonged by NMDA receptor-mediated currents.

We investigated the influence of 2-amino-5-phosphonovalerate (APV), a selective antagonist of the N-methyl-D-aspartate (NMDA) receptor, on the time course of small excitatory postsynaptic potentials (EPSPs) in pyramidal neurones in layer 2/3 of adult rat visual cortex in vitro. Time constants of the voltage decay following the EPSPs (T(s)) and after brief (2 ms) pulses of current injected at the soma (T(p)) were determined from semilogarithmic plots of averages of 100-250 trials. The mean T(s)/T(p) ratio decreased from 1.53 +/- 0.29 (S.D.) to 1.10 +/- 0.08 on addition of 50 microM APV to the bathing medium (P less than 0.001; n = 23), but there was no significant change in EPSP peak amplitude or rise-time. These results suggest that the time course of many small EPSPs, even at negative membrane potentials and in the presence of Mg2+, can be prolonged by NMDA receptor-mediated currents.

Reduction by baclofen of monosynaptic EPSPs in lumbosacral motoneurones of the anaesthetized cat.

1. Monosynaptic excitatory postsynaptic potentials (EPSPs) were elicited in lumbosacral motoneurones of pentobarbitone anaesthetized cats by stimulating group Ia muscle afferents with most of the dorsal roots severed. In some experiments Ia EPSPs were recorded together with monosynaptic EPSPs elicited by stimulating the ipsilateral ventral quadrants (VQ) of the thoracic spinal cord. Injection of (+/-) baclofen (1 mg kg-1 I.V.) caused a reduction in the peak amplitudes of both Ia and VQ EPSPs, which started immediately upon injection and progressed gradually. No recovery in EPSP amplitude was seen during the recording period, which lasted up to 60 min. 2. The Ia EPSP peak amplitude was reduced by 18-61% (mean +/- S.D., 38 +/- 14%; n = 30), while VQ EPSPs were reduced by 7-42% (23 +/- 13%; n = 5). Baclofen had a significantly larger effect on Ia EPSPs than VQ EPSPs (P less than 0.001; t test). 3. Baclofen did not cause any consistent change in the membrane potential, nor in the membrane time constant, as estimated from the exponential decay of the tail of the EPSP. There was no tendency for the reduction in peak EPSP amplitude to be related to the estimated electrical distance on the dendritic tree at which the synaptic current was injected. 4. For two I a and two VQ EPSPs, the trial-to-trial fluctuation in the peak amplitude was resolved into quantal parameters before and after baclofen was administered. The reduction in peak amplitude was in all cases accounted for by a reduction in the probability of release of neurotransmitter, with no change in quantal size. Other EPSPs either showed negligible trial-to-trial amplitude fluctuation, or could not be resolved into quantal parameters without ambiguity. 5. By comparing the variance components of the EPSP peak amplitude distribution, the hypothesis was tested that the entire action of baclofen was to reduce quantal amplitude. This was rejected for sixteen out of thirty Ia and three out of five VQ EPSPs (P less than 0.05). 6. These results support a presynaptic site of action of baclofen on the terminals of Ia afferents, by decreasing the probability of release of neurotransmitter. They also indicate a similar, although weaker, action on VQ terminals. No evidence was found for an action on the postsynaptic membrane properties or synaptic conductance.

Nonuniform release probabilities underlie quantal synaptic transmission at a mammalian excitatory central synapse.

1. Excitatory postsynaptic potentials (EPSPs) evoked by impulses in single group I muscle afferents were recorded in dorsal spinocerebellar tract (DSCT) neurons in the spinal cords of anesthetized cats. Fluctuations in the amplitude of these single-fiber EPSPs were determined from measurements of EPSP peak amplitude and contaminating noise (800-4600 trials). 2. In a previous study at this connection, we found that these single-fiber EPSPs fluctuated in amplitude between approximately equal, or quantal, increments. However, these quantal fluctuations could not be described by simple binomial statistics (39). In the present study we have applied further analysis procedures to the same single-fiber EPSPs to formulate a more appropriate probabilistic model of transmission at this connection. 3. In the first stage we have demonstrated that each single-fiber EPSP is composed of the sum of a number (3-30) of uniform quantal events, and that there is extremely little variability in the amplitude of the single quantal event. 4. In a further procedure, we have demonstrated that these quantal fluctuations can be described by a compound binomial model in which each underlying quantal event is associated with a particular, but independent, release probability. The results of this analysis indicate that the probability of transmitter release varies considerably between release sites at this connection. (The use of such a compound binomial model reemphasized previous warnings concerning the interpretation of the results of all statistical models of quantal release. Problems regarding the non-unique nature of N, the total population of quantal events, and other such difficulties are discussed.) 5. A model of transmission at this connection is proposed, in which there are a number of "active" release sites, exhibiting generally high release probabilities, and a number of "reserve" release sites, with zero, or close to zero, release probability. The physiological consequences of such a scheme are discussed.

Factors that control amplitude of EPSPs in dendritic neurons.

We have used a computer-based mathematical model of alpha-motoneurons and of group Ia synaptic input to them, based on anatomical and electrophysiological data from the cat spinal cord, in order to examine the effects of variations in neuron size and input resistance and of conductance magnitude and duration on the generation of excitatory postsynaptic potentials (EPSPs). The first set of calculations were designed to test the possible role of nonlinear EPSP summation in producing a differential distribution of posttetanic potentiation of group Ia EPSPs, described in the preceding paper (25; see also Refs. 26, 27). The results suggest that the negative correlations observed between the degree of posttetanic potentiation of Ia EPSPs and initial (pretetanic) EPSP amplitude as well as with the input resistance of the postsynaptic motoneurons can be explained in part by the inherent non-linearity between conductance change and the resultant potential change at chemical synapses. In a second set of calculations, we used the same model system to evaluate the effects produced by variations in neuronal membrane area, input resistance, and specific membrane resistivity, as well as of the density of excitatory synaptic input on the peak amplitude of EPSPs. With parameters constrained to match the properties of alpha-motoneurons and group Ia synaptic input, EPSP amplitudes were most sensitive to changes in synaptic density and were much less sensitive to alterations in neuron input resistance and specific membrane resistivity when synaptic density was constant.