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M Frerking

Publications and source records attributed to M Frerking.

18 recordsLinked to original sources
PubMed2006

Functional consequences of presynaptic inhibition during behaviorally relevant activity.

Presynaptic inhibition is a widespread mechanism for regulating transmitter release in the CNS. Presynaptic inhibitors act as a high-pass filter, but the functional consequence of this filtering during the synaptic processing of behaviorally relevant activity remains unknown. Here we use analytical approaches to examine the effects of presynaptic inhibition on synaptic output in response to activity patterns from CA3 pyramidal cells during the performance of a complex behavioral task. We calculate that presynaptic inhibition enhances the contrast between background activity and responses to environmental cues and that neuronal responses to location are subject to stronger contrast enhancement than neuronal responses to olfactory information. Our analysis suggests that presynaptic inhibition also enhances the importance of integrative inputs that respond to many behavioral cues during the task at the expense of specific inputs that respond to only a few of these cues.

Action Potentials↗
PubMed2005

Spike timing in CA3 pyramidal cells during behavior: implications for synaptic transmission.

Spike timing is thought to be an important mechanism for transmitting information in the CNS. Recent studies have emphasized millisecond precision in spike timing to allow temporal summation of rapid synaptic signals. However, spike timing over slower time scales could also be important, through mechanisms including activity-dependent synaptic plasticity or temporal summation of slow postsynaptic potentials (PSPs) such as those mediated by kainate receptors. To determine the extent to which these slower mechanisms contribute to information processing, it is first necessary to understand the properties of behaviorally relevant spike timing over this slow time scale. In this study, we examine the activity of CA3 pyramidal cells during the performance of a complex behavioral task in rats. Sustained firing rates vary over a wide range, and the firing rate of a cell is poorly correlated with the behavioral cues to which the cell responds. Nonrandom interactions between successive spikes can last for several seconds, but the nonrandom distribution of interspike intervals (ISIs) can account for the majority of nonrandom multi-spike patterns. During a stimulus, cellular responses are temporally complex, causing a shift in spike timing that favors intermediate ISIs over short and long ISIs. Response discrimination between related stimuli occurs through changes in both response time-course and response intensity. Precise synchrony between cells is limited, but loosely correlated firing between cells is common. This study indicates that spike timing is regulated over long time scales and suggests that slow synaptic mechanisms could play a substantial role in information processing in the CNS.

Action Potentials↗
PubMed2001

Presynaptic kainate receptors at hippocampal mossy fiber synapses.

Hippocampal mossy fibers, which are the axons of dentate granule cells, form powerful excitatory synapses onto the proximal dendrites of CA3 pyramidal cells. It has long been known that high-affinity binding sites for kainate, a glutamate receptor agonist, are present on mossy fibers. Here we summarize recent experiments on the role of these presynaptic kainate receptors (KARs). Application of kainate has a direct effect on the amplitude of the extracellularly recorded fiber volley, with an enhancement by low concentrations and a depression by high concentrations. These effects are mediated by KARs, because they persist in the presence of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-selective antagonist GYKI 53655, but are blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/KAR antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the KAR antagonist SYM2081. The effects on the fiber volley are most likely caused by a depolarization of the fibers via the known ionotropic actions of KARs, because application of potassium mimics the effects. In addition to these effects on fiber excitability, low concentrations of kainate enhance transmitter release, whereas high concentrations depress transmitter release. Importantly, the synaptic release of glutamate from mossy fibers also activates these presynaptic KARs, causing an enhancement of the fiber volley and a facilitation of release that lasts for many seconds. This positive feedback contributes to the dramatic frequency facilitation that is characteristic of mossy fiber synapses. It will be interesting to determine how widespread facilitatory presynaptic KARs are at other synapses in the central nervous system.

Animals↗
PubMed2001

Kainate receptors depress excitatory synaptic transmission at CA3-->CA1 synapses in the hippocampus via a direct presynaptic action.

Kainate receptor activation depresses synaptic release of neurotransmitter at a number of synapses in the CNS. The mechanism underlying this depression is controversial, and both ionotropic and metabotropic mechanisms have been suggested. We report here that the AMPA/kainate receptor agonists domoate (DA) and kainate (KA) cause a presynaptic depression of glutamatergic transmission at CA3-->CA1 synapses in the hippocampus, which is not blocked by the AMPA receptor antagonist GYKI 53655 but is blocked by the AMPA/KA receptor antagonist CNQX. Neither a blockade of interneuronal discharge nor antagonists of several neuromodulators affect the depression, suggesting that it is not the result of indirect excitation and subsequent release of a neuromodulator. Presynaptic depolarization, achieved via increasing extracellular K(+), caused a depression of the presynaptic fiber volley and an increase in the frequency of miniature EPSCs. Neither effect was observed with DA, suggesting that DA does not depress transmission via a presynaptic depolarization. However, the effects of DA were abolished by the G-protein inhibitors N-ethylmaleimide and pertussis toxin. These results suggest that KA receptor activation depresses synaptic transmission at this synapse via a direct, presynaptic, metabotropic action.

Animals↗
PubMed2001

Restless AMPA receptors: implications for synaptic transmission and plasticity.

A central assumption in neurobiology holds that changes in the strength of individual synapses underlie changes in behavior. This concept is widely accepted in the case of learning and memory where LTP and LTD are the most compelling cellular models. It is therefore of great interest to understand, on a molecular level, how the brain regulates the strength of neuronal connections. We review a large body of evidence in support of the very straightforward regulation of synaptic strength by changing the number of postsynaptic receptors, and discuss the molecular machinery required for insertion and removal of AMPA receptors.

Animals↗
PubMed2000

Synaptic activation of presynaptic kainate receptors on hippocampal mossy fiber synapses.

Kainate receptors (KARs) are a poorly understood family of ionotropic glutamate receptors. A role for these receptors in the presynaptic control of transmitter release has been proposed but remains controversial. Here, KAR agonists are shown to enhance fiber excitability, and a number of experiments show that this is a direct effect of KARs on the presynaptic fibers. In addition, KAR activation inhibits evoked transmitter release from mossy fiber synapses. Synaptic release of glutamate from either neighboring mossy fiber synapses or associational/commisural (A/C) synapses results in the activation of these presynaptic ionotropic KARs. These results, along with previous studies, indicate that KARs, through the endogenous release of glutamate, mediate excitatory postsynaptic potentials (EPSPs), alter presynaptic excitability, and modulate transmitter release.

Animals↗
PubMed2000

Synaptic kainate receptors.

Kainate receptors are a family of ionotropic glutamate receptors with poorly understood functions. Recent evidence firmly establishes kainate receptors as postsynaptic mediators of synaptic transmission. A second, presynaptic, modulatory role of kainate receptors has also been suggested, although the mechanism(s) involved remain controversial.

Animals↗
PubMed1999

Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus.

Kainate (KA) receptor activation depresses stimulus-evoked gamma-aminobutyric acid (GABA-mediated) synaptic transmission onto CA1 pyramidal cells of the hippocampus and simultaneously increases the frequency of spontaneous GABA release through an increase in interneuronal spiking. To determine whether these two effects are independent, we examined the mechanism by which KA receptor activation depresses the stimulus-evoked, inhibitory postsynaptic current (IPSC). Bath application of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)/KA receptor agonist KA in the presence of the AMPA receptor antagonist GYKI 53655 caused a large increase in spontaneous GABA release and a coincident depression of the evoked IPSC. The depressant action on the evoked IPSC was reduced, but not abolished, by the GABA(B) receptor antagonist SCH 50911, suggesting that the KA-induced increase in spontaneous GABA release depresses the evoked IPSC through activation of presynaptic GABA(B) receptors. KA had no resolvable effect on the potassium-induced increase in miniature IPSC frequency, suggesting that KA does not act through a direct effect on the release machinery or presynaptic calcium influx. KA caused a decrease in pyramidal cell input resistance, which was reduced by GABA(A) receptor antagonists. KA also caused a reduction in the size of responses to iontophoretically applied GABA, which was indistinguishable from the SCH 50911-resistant, residual depression of the evoked IPSC. These results suggest that KA receptor activation depresses the evoked IPSC indirectly by increasing interneuronal spiking and GABA release, leading to activation of presynaptic GABA(B) receptors, which depress GABA release, and postsynaptic GABA(A) receptors, which increase passive shunting.

Hippocampus↗
PubMed1999

Differences in uniquantal amplitude between sites reduce uniquantal variance when few release sites are active.

In many types of central neurons, the coefficient of variation (CV) of stimulus-evoked uniquantal events inferred from quantal analysis is small, frequently less than 20%. In contrast, spontaneous putative uniquantal events (minis) from the same neurons are much more variable in amplitude, having a CV of roughly 50% or more. One explanation for this discrepancy is that, if the variance in mini amplitude were generated by differences between release sites, the small number of sites activated during stimulation would sometimes fortuitously have similar quantal amplitudes. Only in these fortuitous cases where uniquantal variance is small could quantal peaks be resolved, and therefore the uniquantal CV seen in the subset of cells where quantal analysis can be performed would systematically be much smaller than predicted by the mini distribution. We have explored this possibility by Monte Carlo simulation assuming all variance in mini amplitude to be due to intersite differences in uniquantal amplitude. We find that when a small number of release sites are activated under these conditions, there is a reduction in the expected uniquantal variance. However, the expected uniquantal CV is highly variable from one experiment to the next, and low uniquantal CVs are not expected to be seen often enough to account for the high frequency with which quantal peaks with a uniquantal CV < 20% are observed experimentally. We conclude that variance in mini amplitude between release sites cannot account for the small uniquantal CV seen in quantal analysis of many central synapses.

Hippocampus↗
PubMed1998

Synaptic activation of kainate receptors on hippocampal interneurons.

Although kainate receptor activation has been known to evoke epileptiform activity, little is known about the role of kainate receptors in synaptic transmission. Here we report that kainate (KA) receptors are present on interneurons and, when activated, cause a large increase in the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) driven by action potentials. Stimulation of excitatory afferents generates a pharmacologically identifiable synaptic current mediated by KA receptors in interneurons. This synaptic current is similar to that mediated by AMPA receptors in its response to short stimulus trains, current-voltage relations and coefficient of variation, but it is much smaller in peak amplitude and much slower. KA application also considerably depresses evoked IPSCs. This depression seems to be in large part an indirect consequence of the repetitive firing evoked by the activation of the interneuronal somatic/dendritic KA receptors.

Animals↗
PubMed1998

Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus.

Brain-derived neurotrophic factor (BDNF) modulates inhibitory, but not excitatory, transmission in the CA1 region of the hippocampus. J. Neurophysiol. 80: 3383-3386, 1998. Brain-derived neurotrophic factor (BDNF) has been reported to have rapid effects on synaptic transmission in the hippocampus. We report here that bath application of BDNF causes a small but significant decrease in stimulus-evoked inhibitory postsynaptic currents (IPSCs) on CA1 pyramidal cells, which is prevented by the tyrosine kinase inhibitor lavendustin A. BDNF causes a decrease in the 1/CV2 of the IPSC, and also reduces paired-pulse depression of the IPSC, suggesting a presynaptic site of action. In contrast, BDNF did not have a detectable effect on field excitatory postsynaptic potentials measured in stratum radiatum. We conclude that BDNF has a selective depressant action on inhibitory transmission in the hippocampus, due at least in part to a presynaptic mechanism.

Animals↗
PubMed1997

Are some minis multiquantal?

The amplitude distribution of miniature postsynaptic currents (minis) in many central neurons has a large variance and positive skew, but the sources of this variance and skew are unresolved. Recently it has been proposed that spontaneous Ca2+ influx into a presynaptic bouton with multiple release sites could cause spontaneous multiquantal minis by synchronizing release at all sites in the bouton, accounting for both the large variance and skew of the mini distribution. We tested this hypothesis by evoking minis with internally perfused, buffered Ca2+ and the secretagogue alpha-latrotoxin, both in the absence of external Ca2+. With these manipulations, the synchronized release model predicts that the mini distribution should collapse to a Gaussian distribution with a reduced coefficient of variation. Contrary to this expectation, we find that mini amplitude distributions under these conditions retain a large variance and positive skew and are indistinguishable from amplitude distributions of depolarization-evoked minis, strongly suggesting that minis are uniquantal.

Animals↗
PubMed1996

Effects of variance in mini amplitude on stimulus-evoked release: a comparison of two models.

The strength of synaptic connections between two neurons is characterized by the number of release sites (N) on the presynaptic cell, the probability (p) of transmitter release at those sites in response to a stimulus, and the average size (A) of the postsynaptic response from each site. Quantal analysis can determine N, p, and A, but the large variance in the amplitudes of minis at central synapses is predicted to obscure quantal peaks and render quantal analysis unusable. Recently it has been suggested that the variance in mini amplitude is generated by differences between release sites, rather than by quantum-to-quantum fluctuations at identical sites, and that this form of variance in mini amplitude reduces the amount of variance expected in quantal peaks. Using simulations, we examine the possibility of resolving quantal peaks assuming either form of variance in mini amplitude. We find that individual quantal peaks are resolvable in neither case, provided that the uniquantal distribution is similar to the mini distribution. Because this lack of resolution compromises the utility of quantal analysis, we develop a general description that can solve N and p, given the statistical parameters of the mini distribution and the evoked distribution. We find that this description is relatively insensitive to the source of variance in mini amplitude.

Analysis of Variance↗
PubMed1996

Saturation of postsynaptic receptors at central synapses?

A fundamental issue in synaptic physiology is whether the postsynaptic response to a quantum of transmitter is limited by the number of receptors available. Fierce debate over the past few years has yielded no consensus. The majority of evidence suggests that the degree of receptor occupancy is likely to be sensitive to a number of factors, including the detailed anatomy of the synaptic cleft and the time course of transmitter clearance, and is probably different from one synapse to the next.

Animals↗
PubMed1995

Variation in GABA mini amplitude is the consequence of variation in transmitter concentration.

Miniature postsynaptic currents (minis) in cultured retinal amacrine cells, as in other central neurons, show large variations in amplitude. To understand the origin of this variability, we have exploited a novel form of synapse in which pre- and postsynaptic receptors sample the same quantum of transmitter. At these synapses, mini amplitudes measured simultaneously in the 2 cells show a strong correlation, accounting for, on average, more than half of the variance in amplitude. Two pieces of evidence support the conclusion that variations in the amount of transmitter in different quanta underlie this correlation. First, diazepam, which enhances GABA binding, increases mini amplitude, implying therefore that transmitter concentration is not saturating. Second, we show that amplitude distributions from all cells, even those with a small number of release sites, have the same shape, implying that most or all variance is intrinsic to each release site.

Animals↗
PubMedDate not supplied

Neurotensin induces calcium oscillations in cultured amacrine cells.

The peptide, neurotensin, is found in a class of amacrine cells synapsing chiefly with other amacrine cells in the chicken retina (Li & Lam, 1990; Watt et al., 1991). To investigate the possible effects of neurotensin, we have used Ca2+ imaging to measure cytosolic Ca2+ concentrations in cultured chick amacrine cells. Following a delay of about 2 min, neurotensin (300 nM) induced oscillations in Ca2+ concentration that typically had a period of 2 min and peak values of about 300 nM when averaged over the cell body. The phospholipase C inhibitors U-73, 112 and 4'-bromophenacyl bromide terminated oscillations induced by neurotensin but the protein kinase inhibitors H7 and staurosporine did not inhibit oscillations, increasing their frequency instead. In the absence of external Ca2+, neurotensin induced only a single Ca2+ transient, much briefer than when external Ca2+ was present. Together these results suggest that neurotensin activates phospholipase C, thereby producing IP3 that triggers Ca2+ release from an internal store. Although this released Ca2+ contributes to periodic Ca2+ peaks, the majority of cytosolic Ca2+, even in the first peak, comes from Ca2+ influx across the plasmalemma.

Amino Acid Sequence↗