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D S Faber

Publications and source records attributed to D S Faber.

At least 19 recordsLinked to original sources
PubMed1995

"Latent" inhibitory connections become functional during activity-dependent plasticity.

Simultaneous pre- and postsynaptic recordings from identified glycinergic inhibitory interneurons and the Mauthner cell showed that 25% of the afferents produced no or extremely small postsynaptic responses. Morphological determination of the number of contacts made by these cells on the Mauthner cell revealed a connectivity similar to that of functional neurons which always produce clear inhibitory postsynaptic potentials, suggesting that most of the endings, made by weak interneurons are silent. Intraaxonal injection of 4-aminopyridine or Ca2+ greatly enhanced transmission at functional connections but did not modify those which were ineffective. However, after eighth nerve tetanic stimuli, transmission at the weak connections was unmasked or enhanced for prolonged periods and was twice as likely to be potentiated, with a 6-fold greater mean enhancement than the potent ones. This result provides additional support for long-term potentiation of inhibitory synapses. Furthermore, weakly functional junctions represent a "reserve" pool which can be critical for the expression of plasticity within a network, and, consequently, for setting the threshold of reflex activities such as the escape reaction mediated by the Mauthner cell.

4-Aminopyridine↗
PubMed1995

Retrograde synaptic communication via gap junctions coupling auditory afferents to the Mauthner cell.

Large myelinated club endings of the goldfish eighth nerve arise in the sacculus and establish mixed electrotonic and chemical synapses with the distal part of the Mauthner (M-) cell's lateral dendrite. We show here, using paired pre- and postsynaptic recordings, that depolarizing currents generated postsynaptically (specifically, the mixed synaptic potential produced by activation of part of the afferent population) can in some cases excite the presynaptic fibers and cause them to backfire. Strikingly, while in some systems junctional properties prevent the antidromic spread of depolarizing currents, physiological properties of these afferents and the gap junctions promote backfiring: the amplitude of the coupling potential recorded from an afferent fiber is voltage dependent, increasing with depolarization and being reduced during hyperpolarization. Two mechanisms, with different kinetics, underlie this voltage dependence. One, a nonlinear membrane property of the afferent fiber itself, enhances the coupling potential as the afferent membrane depolarizes. The second mechanism, which is less sensitive to voltage and is symmetric about the resting potential, most likely represents voltage dependence of the junctional membrane. Additionally, we also show retrograde diffusion of low molecular weight substances, as the fluorescent dye Lucifer yellow and the tracer Neurobiotin were found in the terminals of afferent fibers after being injected postsynaptically into the M-cell. These results suggest that the gap junctions in these primary afferents are not only involved in fast anterograde synaptic transmission but also provide the substrate for a retrograde intercellular communication. The electrical coupling may modify the input-output relation between eighth nerve afferents and the lateral dendrite by synchronizing the population of already active fibers and by promoting the recruitment of new fibers via backfiring, such that weaker inputs produce relatively larger responses.

Animals↗
PubMed1994

Automatic detection of spontaneous synaptic responses in central neurons.

A fully automatized software package for detection and measurements of randomly occurring synaptic transients embedded in background noise is described. It is based on waveform recognition protocols, allows analysis of long data segments, and provides quantitative information about event amplitudes and kinetics. Simulated postsynaptic recordings have been used to assess its performance over a wide range of conditions mimicking those seen in physiological experiments.

Animals↗
PubMed1994

Weak excitation and simultaneous inhibition induce long-term depression in hippocampal CA1 neurons.

1. Weak excitation to rat hippocampal CA1 neurons via Schaffer collaterals at a frequency of 0.1 or 0.2 Hz accompanied by repeated brief exposures to the inhibitory transmitter gamma-amino-butyric acid (GABA) causes a long-term depression (LTD, up to 90% of the control) of the stimulated pathway. This depression can be reversed by high-frequency stimulation. 2. Although inhibition is necessary for the induction of this LTD, the depression can be produced with either the GABAA or the GABAB receptor agonists. 3. This conjunctive LTD could not be blocked by the N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovaleric acid. 4. It was, however, blocked by the metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid and (RS)-alpha-methyl-4-carboxyphenylglycine, indicating that activation of a metabotropic glutamate receptor is necessary for the LTD. Induction also appeared to require an intracellular Ca2+ increase. 5. Because GABAergic inhibition often modulates glutamatergic transmission in the brain, we propose that this form of synaptic modification is of potential importance for neural plasticity.

Animals↗
PubMed1994

Postsynaptic modulation of synaptic efficacy at mixed synapses on the Mauthner cell.

Extracellular application of dopamine in the synaptic bed of the lateral dendrite of the goldfish Mauthner (M-) cell enhances both the electrical and chemical components of the mixed excitatory postsynaptic potential (EPSP) evoked by ipsilateral eighth nerve stimulation (Pereda et. al., 1992). We describe here results of experiments designed to determine the locus of action of dopamine and the underlying cellular mechanisms. This amine acts independently on the two modes of transmission, since (1) the percentage increases in the two were not correlated, (2) the time courses of their modifications were independent, and (3) the observed increases in synaptic responses cannot be attributed to a generalized effect on M-cell input conductance, which was increased by dopamine, a change that would rather be expected to shunt the synaptic potentials. Also, dopamine does not produce presynaptic spike broadening and does not modify paired-pulse facilitation, two indications that it acts postsynaptically. The alterations in the mixed EPSP are presumably due to activation of a postsynaptic cAMP-dependent phosphorylation pathway. Specifically, they did not occur if the cAMP-dependent protein kinase inhibitor PKI5-24 was injected intradendritically prior to dopamine application, and they could, on the other hand, be mimicked by injections of the catalytic subunit of the cAMP-dependent protein kinase, PKACAT. In contrast, neither manipulation altered the M-cell input conductance directly or affected the dopamine-induced increase in conductance, suggesting this effect of dopamine is cAMP independent.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1993

GABA responses and their partial occlusion by glycine in cultured rat medullary neurons.

Whole-cell current responses to bath application of GABA and glycine were studied in medullary neurons cultured from embryonic rats. Two current components were seen in the responses to bath application of GABA, one component which desensitized and another which did not. These two current components have different dose-response characteristics for GABA, with the nondesensitizing component being activated more effectively and reaching its peak amplitude at lower agonist concentrations than the desensitizing one. The agonist concentrations producing half of the maximum responses are 2.8 +/- 0.3 (+/- S.E.M., n = 9) and 14.7 +/- 2.7 (n = 5) microM for the nondesensitizing and desensitizing components, respectively. The two current components for GABA are differentially affected by the antagonists, picrotoxin and bicuculline. The antagonist concentrations which block 50% of the control desensitizing and nondesensitizing responses to GABA are 33 and 320 microM for picrotoxin, and 3 and 50 microM for bicuculline, respectively. Thus, the characteristics of the GABA responses are analogous to those described previously for glycine in that there are two components which are differentially sensitive to agonist concentration [Lewis et al. (1991) J. Neurophysiol, 40, 1178-1187]. We now find there is occlusion between the responses to GABA and glycine, indicating that they share a population of receptors or channels. The occlusion was incomplete (< 80%) in half of the cells, suggesting that both agonists also activate unique receptors. Furthermore, the current responses to 35 microM GABA are blocked by the glycinergic antagonist, strychnine, with half-maximal blocking concentrations equal to 2 and 30 microM for the desensitizing and nondesensitizing components, respectively. This strychnine sensitivity is less than that for the glycine receptor. At the same time, the current responses to 100 microM glycine are sensitive to the GABAergic antagonists, picrotoxin and bicuculline. The half-maximal blocking concentrations are 36 and 120 microM picrotoxin, and 120 and 500 microM bicuculline, for the desensitizing and nondesensitizing components of the glycine response, respectively. Consequently, these results suggest that these cultured cells have at least three types of inhibitory receptors: glycine receptors, GABA receptors and GABA/glycine receptors, with all three receptors sensitive to block by strychnine, bicuculline and picrotoxin. The GABA/glycine receptor may be an immature form of the inhibitory receptor. Alternatively, some GABA and glycine receptors may have common ionophores.

Animals↗
PubMed1993

Synaptic noise and multiquantal release at dendritic synapses.

1. The quantal nature of inhibitory synaptic noise recorded intracellularly from the lateral dendrite of the goldfish Mauthner cell was studied, using new detection and measurement procedures that eliminate operator intervention. In addition, we employed an analytical algorithm, not previously applied to this problem, which treats composite amplitude distributions as mixtures of gaussians of unknown separations and variances. 2. As in the soma of this neuron, the dendritic inhibitory noise is quantal, with the exception that in the dendrite multiple equally spaced classes may persist in the presence of tetrodotoxin (TTX), an observation that may be correlated with the finding that the inhibitory afferents at this level often contain more than one release site. The validity of the analysis was confirmed by superfusing with saline containing low calcium and high magnesium, which reduces composite histograms that are gaussian mixtures to a single class, equal in amplitude to that of the first component detected in the control. 3. These results suggest that spontaneous exocytotic events may be synchronized at adjacent active zones within single terminals and that lowering the probability of release by reducing calcium may then be a more effective method for isolating single miniature events than is TTX.

Animals↗
PubMed1992

Dopamine enhances both electrotonic coupling and chemical excitatory postsynaptic potentials at mixed synapses.

The transmitter dopamine reduces electrotonic coupling between retinal horizontal cells and increases their sensitivity to glutamate. Since in other systems single afferents establish mixed electrotonic and chemical excitatory synapses with their targets, dopamine might be expected there to depress one component of excitation while enhancing the other. This hypothesis was tested by applying dopamine locally in the vicinity of the lateral dendrite of the goldfish Mauthner cell (M cell) and monitoring the composite electrotonic and chemical excitatory postsynaptic potentials and currents evoked by ipsilateral eighth nerve stimulation. Dopamine produces persistent enhancements of both components of the postsynaptic response while it also increases input conductance. All these dopamine actions are prevented by superfusing the brain with saline containing the dopamine D1 receptor antagonist SCH-23390. Postsynaptic injections of the cAMP-dependent protein kinase inhibitor (Walsh inhibitor, or PKI5-24) block the dopamine-induced changes in synaptic transmission, implicating a cAMP-dependent mechanism. Furthermore, there is a dopaminergic innervation of the M cell, as demonstrated immunohistochemically with antibodies against dopamine and the rate-limiting enzyme in its synthetic pathway, tyrosine hydroxylase. Varicose immunoreactive fibers lie in the vicinity of the distal part of the lateral dendrite between the large myelinated club endings that establish the mixed synapses. As determined with electron microscopy, the dopaminergic fibers contain small vesicles, and they do not have synaptic contacts with either the afferents or the M cell, remaining instead in the synaptic bed. Taken together, these results suggest that dopamine released at a distance from these terminals increases the gain of this primary sensory input to the M cell, most likely through a phosphorylation mechanism.

Animals↗
PubMed1992

Intrinsic quantal variability due to stochastic properties of receptor-transmitter interactions.

Synaptic events at the neuromuscular junction are integer multiples of a quantum, the postsynaptic response to transmitter released from one presynaptic vesicle. At central synapses where quanta are small, it has been suggested they are invariant due to occupation of all postsynaptic receptors, a concept neglecting inherent fluctuations in channel behavior. If this did occur, the quantal release model would not apply there and could not be used to localize sites of synaptic modification. Monte Carlo simulations of quanta include transmitter diffusion and interactions with postsynaptic receptors that are treated probabilistically. These models suggest that when there are few postsynaptic channels available at a synapse, their stochastic behavior produces significant intrinsic variance in response amplitude and kinetics, and saturation does not occur. These results were confirmed by analysis of inhibitory quanta in embryonic and adult Mauthner cells involving a small and large number of channels, respectively. The findings apply to excitatory synapses as well.

Animals↗
PubMed1992

Long-term potentiation of inhibitory circuits and synapses in the central nervous system.

Glycinergic inhibition evoked disynaptically in the teleost Mauthner cell by stimulation of the contralateral eighth nerve exhibits long-term potentiation following classical tetanization of that pathway. This enhancement occurs at the synapses between primary afferents onto second-order interneurons and the connections between these inhibitory cells and the Mauthner neuron. The evidence for modifications of glycinergic transmission is that the slope of the relation between the presynaptic volley and the synaptic conductance can be greater after the tetanus. This increase in gain is still manifest after pharmacological block of potentiation at the excitatory synapse with glutamate antagonists. Inhibitory long-term potentiation is induced by tetani weaker than those required for enhancement of the monosynaptic excitation of the other (ipsilateral) Mauthner cell. Thus, in vivo learning can alter the balance between excitation and inhibition within a network by modifying one or both of them.

Animals↗
PubMed1991

Initial synaptic efficacy influences induction and expression of long-term changes in transmission.

Long-term depression (LTD) of glutamatergic and electrotonic transmission can be induced at mixed synapses between eighth nerve fibers and the goldfish Mauthner (M) cell in vivo, by pairing weak presynaptic tetani with postsynaptic inhibition. This LTD can be reversed by stronger tetani that produce long-term potentiation (LTP). Moreover, the depression is more likely to occur and tends to last longer when the initial synaptic efficacy is high--that is, if the synaptic strength is first potentiated. In addition, when synaptic efficacy is initially elevated, a weak tetanization that usually results in a gradually developing potentiation instead produces no change in chemical transmission and even a depression of electrotonic coupling. Thus, the modifications in synaptic transmission caused by a certain tetanizing protocol depend upon the history of synaptic efficacy. This last concept provides an experimental basis for theoretical models concerned with pre- and postsynaptic contributions to the regulation of synaptic plasticity.

Animals↗
PubMed1991

Quantal analysis and synaptic efficacy in the CNS.

Quantal analysis of synaptic transmission at connections between neurons in the CNS has provided insights concerning the structural constraints on transmitter release and postsynaptic responsiveness. However, it has proven difficult in many cases to resolve the size and variability of a single quantum or to distinguish clear peaks in amplitude histograms of evoked responses, due in part to the superposition of background instrumental and biological noise. These limitations raise questions about recent attempts to use direct or indirect methods of quantal analysis in order to distinguish between pre- and postsynaptic loci of the modifications underlying long-term potentiation, particularly since the interpretations are model-dependent and the statistical treatments and experimental techniques employed incorporate simplifying assumptions not yet proven.

Animals↗
PubMed1991

Applicability of the coefficient of variation method for analyzing synaptic plasticity.

The classical coefficient of variation method for "quantal" analysis of synaptic responses allows unambiguous identification of pre- and postsynaptic loci underlying synaptic plasticity only when extensive simplifying restrictions are made. They include invariance of quantal parameters and the assumption that a single afferent produces the evoked potentials or currents. More general theoretical formulations and simulations demonstrate that the standard criteria do not always provide useful guidelines because when the other sources of physiological variance are included, putative pre- and postsynaptic domains may overlap. For example, data typically interpreted as indicating modifications at both sites can be due to a mechanism localized to only one of the two, if parameter variances are taken into consideration in the case of a single input cell, or if there are multiple inputs and the stimulus does not activate all of them reliably. With this perspective, other physiologically realistic hypotheses relevant to the expression of synaptic plasticity, such as that during long-term potentiation, can be envisioned.

Animals↗
PubMed1991

Silent synaptic connections and their modifiability.

Comparison of the two afferent systems illustrates certain features common to synaptic transmission as well as differences that might be important for synaptic plasticity. Transmission at both the inhibitory and excitatory connections is satisfactorily described by a simple binomial model that considers the average probability of release to be the same at each active site, although it should be stressed that the best evidence derives from the first set of afferents. Another similarity between the two systems is that short-term changes in synaptic efficacy, namely, facilitation and depression, appear to be due to changes in p. We previously suggested that both phenomena occur during repetitive stimulation, with the dominant effect depending upon the initial probability of release. It remains to be seen if depression dominates at other inhibitory connections, although it is already clear that one cannot generalize about excitation, because some excitatory junctions have an initial high p and exhibit a marked depression rather than the facilitation described here. We have found no evidence for the notion that some synapses within a connection may be silent. That idea has been proposed, but not proven, for other synaptic connections in the vertebrate central nervous system. Indeed, it will be difficult to assess as long as quantal release cannot be reliably detected at these junctions, and morphological confirmation at the ultrastructural level will also be required. On the other hand, evidence from a few peripheral junctions where one presynaptic afferent establishes hundreds of contacts with its target cell, does suggest the possibility of silent synapses, or at least an extremely low probability of release in those cases. These situations may correspond to extremes of our finding that as the number of release sites increases, p decreases. Regardless, the inverse relation between n and p suggests caution should be exercised in interpreting data indicating that synaptic plasticity is associated with increased numbers of synapses between two cells. Although we have not detected silent synapses within a transmitting connection, we have observed chemically silent connections between neurons, and the evidence reviewed here suggests transmission may be blocked postsynaptically, as with the inhibitory connections, or presynaptically, as with the excitatory ones. Although the underlying mechanisms are only partially elucidated, it is also clear that such connections can be switched into a transmitting mode. Consequently, they may provide a significant reserve that might well become functional in different behavioral states or in response to certain patterns of activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

A characterization of glycinergic receptors present in cultured rat medullary neurons.

1. Whole-cell current responses to bath application of glycine, beta-alanine, and taurine were studied in medullary neurons cultured from embryonic rats. 2. Two current components were seen in the responses to bath application of agonist, one component that desensitized and another that did not. 3. The two current components have different dose-response characteristics, with the nondesensitizing component being activated more effectively at lower concentrations than the desensitizing component and also reaching its peak at lower concentrations. The agonist concentrations producing half-maximal responses are 26 +/- 4 (SE, n = 6) and 69 +/- 17 (n = 7) microM for the nondesensitizing and desensitizing components, respectively, for glycine; 54 +/- 7 (n = 9) and 127 +/- 37 (n = 7) microM for beta-alanine; and 153 +/- 24 (n = 9) 443 +/- 99 (n = 3) microM for taurine. Thus, for each component, the order of potency is glycine greater than beta-alanine greater than taurine. 4. When total responses to glycine, beta-alanine, and taurine are compared in the same cells, taurine and beta-alanine are less potent agonists than glycine, with relative potencies of 1:0.4:0.1 for glycine-beta-alanine-taurine. 5. The desensitizing component is more sensitive to strychnine than the nondesensitizing one. The strychnine concentrations that block 50% of the response to a control dose of agonist are 15 and 500 nM for the desensitizing and nondesensitizing components, respectively, for glycine; 60 nM and 1 microM for beta-alanine; and 18 and 500 nM for taurine. 6. The complete occlusion between the responses to glycine and beta-alanine or glycine and taurine suggests that these agonists activate the same receptors. 7. The two current components may be manifestations of one receptor population with complicated kinetics or two independent receptor populations.

Animals↗
PubMed1991

Role of medullary networks and postsynaptic membrane properties in regulating Mauthner cell responsiveness to sensory excitation.

A benefit of studying well-defined networks at a cellular level is that it might be possible both to place these details in the context of the specific function of the network and to extract general principles applicable to more complex systems. The Mauthner cell system in teleosts is one such vertebrate network where a single impulse can trigger a vital escape reaction, the C start, in response to auditory or visual stimuli. We review here experiments concerned with the organization, at the cellular level, of the afferent circuits impinging on the Mauthner cell and with certain intrinsic membrane properties of the Mauthner cell that contribute to shaping the threshold and expression of the C start. One concept that emerges is related to the interaction between excitatory and inhibitory drives to the Mauthner cell. It seems that every major afferent drive to this neuron also excites a feedforward inhibitory network which, in turn, exerts a major role in establishing and regulating the threshold of the escape response. This design feature is complemented by the Mauthner cell's membrane properties which contribute to the behavioral threshold but exhibit nonlinearities, as excitation begins to overcome inhibition. Finally, we have compared in detail the frequency-dependent characteristics of inhibition and excitation, as revealed by studies of individual identified synaptic connections. This comparison emphasizes the notion that although inhibition is maximized for weak transient stimuli, it becomes depressed at auditory stimulus frequencies that facilitate excitatory transmission and evoke the escape response.

Acoustic Stimulation↗