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W B Levy

Publications and source records attributed to W B Levy.

At least 55 records · Page 3Linked to original sources
PubMed1992

Electrophysiological and pharmacological characterization of perforant path synapses in CA1: mediation by glutamate receptors.

1. With the use of hippocampal slices from adult rats, we studied monosynaptic potentials in CA1 evoked by stimulating either the perforant pathway or the Schaffer collaterals. Excision of region CA3 and the dentate gyrus prevented polysynaptic excitation of CA1 and facilitated interpretation of the extracellular potentials. 2. Laminar profiles distinguished the population excitatory postsynaptic potentials (pEPSPs) in CA1 evoked by stimulating the Schaffer collaterals and the perforant path. Stimulating the perforant path evoked short-latency negative-going pEPSPs in s. lacunosum-moleculare of CA1 and positive-going pEPSPs in s. radiatum. Stimulating the Schaffer collaterals evoked negative-going pEPSPs in s. radiatum. 3. A pharmacological manipulation also distinguished the two pathways in CA1. The selective GABAB agonist baclofen greatly decreased the slope of pEPSPs evoked by stimulating the Schaffer collaterals but did not decrease the slope of pEPSPs evoked by stimulating the perforant path. 4. Combined bath application of the glutamate receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 2-amino-5-phosphonopentanoic acid (APV) abolished the negative-going pEPSPs in s. lacunosum-moleculare evoked by stimulating the perforant pathway. This application of DNQX and APV revealed a positive-going field potential that was blocked by bath application of the gamma-aminobutyric acid (GABA) receptor antagonists picrotoxin or bicuculline. 5. Although the glutamate-mediated component of the response evoked by stimulating the perforant path was apparently excitatory, we never observed a population spike in s. pyramidal evoked by stimulating the perforant path.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1991

LTP-associated EPSP/spike dissociation in the dentate gyrus: GABAergic and non-GABAergic components.

The induction of long-term potentiation (LTP) in the dentate gyrus (DG) leads to a change in the firing characteristics of the dentate granule cells. This phenomenon, termed EPSP/spike dissociation, is seen in field potential studies as a shift to the left of the E-S curve, in which population spike amplitude is plotted against pEPSP slope at various stimulus intensities. It has been suggested that EPSP/spike dissociation reflects a decrease in feed-forward inhibition. To test this hypothesis, we blocked GABA-A neurotransmission in a circumscribed area of the DG in urethane-anaesthetized rats by inserting a micropipette filled with 8 mM bibuculline methiodide in saline. We then recorded E-S curves from 9 such electrodes and from 8 control electrodes before and after inducing LTP in the perforant path. Bicuculline prevented the LTP-associated leftward shift of the E-S curves. Instead, the E-S curve showed a consistent shift to the right at the bicuculline sites after LTP, reflecting potentiation of the pEPSP without corresponding increases in the population spike amplitude. The results indicate that the EPSP/spike relationship is controlled largely by GABAergic input, and that potentiation of the population spike in the DG depends largely on a change in the EPSP/spike relationship.

Action Potentials↗
PubMed1991

NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat.

The present study tested the effect of two non-competitive NMDA receptor antagonists, ketamine and phencyclidine, on the induction of long-term depression (LTD) in the dentate gyrus of urethane-anesthetized rats. Both drugs blocked the induction of LTD as well as long-term potentiation (LTP). NMDA receptor activation thus seems to be required for the induction of both LTD and LTP in the dentate gyrus. High-intensity conditioning stimulation did not overcome the phencyclidine block of LTD. Strong, but brief, postsynaptic depolarization is apparently not the only event needed to trigger LTD.

Anesthesia, General↗
PubMed1991

Refining the temporal definition of an association at the neuronal level using long-term potentiation and long-term depression in the dentate gyrus.

This study sharpens the temporal definition of an association in the context of long-term synaptic modification of the monosynaptic projections from entorhinal cortex to dentate gyrus in the anesthetized rat. The ipsilateral projection produces a powerful postsynaptic excitation and shows synaptic potentiation following 7.5 ms trains. On the other hand, brief, high-frequency contralateral stimulation just after this powerful postsynaptic excitation is followed by long-term depression (LTD) at the synapses of this pathway. Therefore, based on the differential induction of long-term potentiation (LTP) or LTD, a cell can distinguish associated pre- and postsynaptic activation at a temporal resolution at least as small as 7.5 ms.

Animals↗
PubMed1990

Blockade of inhibition in a pathway with dual excitatory and inhibitory action unmasks a capability for LTP that is otherwise not expressed.

Long-term potentiation (LTP) can be readily elicited in a number of hippocampal pathways, but has not been seen in the dentate commissural pathway. The dentate commissural pathway is similar to the commissural/Schaffer collateral projection to CA1 except that it produces powerful inhibition that occurs nearly concurrently with the excitation. The present study evaluates whether this inhibition prevents the pathway from expressing LTP. Acute neurophysiological experiments were carried out in urethane anesthetized rats. To locally block inhibition in the dentate gyrus, a recording micropipette filled with 8 mM bicuculline was positioned in the dentate gyrus. A control saline-filled micropipette was positioned nearby. The commissural pathway was activated by stimulating electrodes in the contralateral CA3/CA4 region. Brief high-frequency stimulation of the commissural pathway reliably elicited LTP at the bicuculline electrode but not at the control electrode. This LTP required a threshold level of stimulation for its initiation, suggesting that like most other examples of LTP, the LTP in the commissural system depended upon activation of a voltage-dependent receptor. The high-frequency stimuli used to induce LTP produced an extracellular negativity at the bicuculline electrode that was not present at the control electrode. This negative potential was selectively blocked by ketamine and MK801, suggesting that the negative potential reflects N-methyl-D-aspartate (NMDA) receptor activation. Taken together, these results suggest that LTP is not normally expressed by the dentate commissural pathway because the simultaneous inhibition prevents the depolarization-related relief of Mg2+ blockade of the NMDA receptor.

Animals↗
PubMed1990

Associative synaptic potentiation and depression: quantification of dissociable modifications in the hippocampal dentate gyrus favors a particular class of synaptic modification equations.

This report further characterizes associative long-term synaptic modification of the ipsilateral and contralateral synapses formed by the bilateral entorhinal cortical (EC) projection to the dentate gyrus (DG). The experimental model is the anesthetized hooded rat. The quantitative results qualify this system as a model for studying the rules of associative synaptic modification formulated in terms of individual synapses. Bilateral DG microelectrodes recorded both ipsilateral and contralateral EC-DG responses before and after brief, high-frequency EC conditioning stimulation. The weak contralateral pathway received high-frequency conditioning before, during, or after similar conditioning of the strong, converging ipsilateral pathway. Statistical analyses revealed two types of significant, dissociated synaptic modifications, which depend on the relationship of the ipsilateral and contralateral afferents. First, contralateral EC-DG responses potentiated or depressed when the converging ipsilateral responses concurrently either potentiated or remained unchanged. Second, contralateral EC-DG responses potentiated, depressed, or showed no change when the collateral ipsilateral responses concurrently either potentiated or remained unchanged. Correlation and contingency table analyses indicated that changes in the contralateral synaptic responses are not well predicted by changes at either neighboring synapses of the converging ipsilateral pathway or at synapses of the collateral ipsilateral pathway. The contingencies of associated pre- and postsynaptic activation determined by the conditioning paradigm, however, accurately predicted the altered synaptic responses of both ipsilateral and contralateral EC-DG pathways. The results imply that associative synaptic modification in the EC-DG system is specific to individual synapses and requires both appropriate presynaptic and postsynaptic activation. Because this system provides suitable controls for nonspecific effects of conditioning stimulation and because modification of neighboring synapses is dissociable, the EC-DG system can be used to study further those rules of activity-dependent associative modification that are formulated in terms of individual synapses. The discussion briefly considers published rules of synaptic modification, pointing out several rules that are not consistent with the experimental observations and one that agrees with the present results.

Animals↗
PubMed1990

Morphological correlates of long-term potentiation imply the modification of existing synapses, not synaptogenesis, in the hippocampal dentate gyrus.

This report evaluates two morphological markers of synaptogenesis following the induction of long-term potentiation (LTP) in the dentate gyrus of the anesthetized rat. These two morphological features, polyribosomes and multiple synaptic contacts, are known to increase in number with synaptogenesis in the mature hippocampus. The analysis focused on the middle third of the dentate molecular layer. As shown previously, this is the region of primary synaptic activation in our electrophysiological protocol and the region of localized morphological changes with LTP. Here the incidence of a polyribosome at the base of a dendritic spine declined 57% with LTP. In addition, the number of multiple synaptic contacts decreased 18% there with LTP. Both decreases were more pronounced immediately following conditioning stimulation than at later intervals. Because both morphological features decrease with LTP but increase with synaptogenesis, the data do not support the hypothesis that new synapses form with LTP. Instead, the data add further support to the view that the strengthening of existing excitatory synapses underlies LTP.

Action Potentials↗
PubMed1990

Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes.

1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1990

Spatial overlap between populations of synapses determines the extent of their associative interaction during the induction of long-term potentiation and depression.

1. This study evaluates the associative interactions between inputs that lead to long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG). Previous studies have revealed that when two inputs are coconditioned, the extent of LTP is greater than when each input is conditioned alone. Moreover, for a weak input that does not show LTP when conditioned alone, LTP can be induced in that weak input if it is coconditioned with a strong input. LTD results when one input is silent when another is conditioned. In the present study, we evaluate whether these associative interactions depend on the extent of overlap of the terminal fields of the different inputs. 2. The experiment took advantage of the topographical organization of the temporodentate pathway from the entorhinal cortex (EC) to the DG. Four stimulating electrodes were placed so as to activate ipsilateral and crossed components of the projections from medial and lateral portions of the EC. Recording electrodes were positioned unilaterally in the DG so as to record field potentials. The localization of the synaptic field that was activated by each electrode was determined by current source density (CSD) analysis. The extent of overlap between the terminal fields of ipsi- and contralateral pathways was assessed, and the pathways were divided into groups where the overlap between current sinks was 0-50 or 51-100%. 3. Conditioning stimulation (400-Hz trains of 8 pulses delivered 8 times) was delivered to pathways alone or in combination with other pathways. The extent of LTP was evaluated after coactivation of pathways that overlapped substantially (51-100%) or minimally (0-50%). The extent of LTD was evaluated in pathways that were silent during conditioning of other overlapping or nonoverlapping pathways. 4. The extent of associative LTP or LTD depended on the extent of overlap between the terminal fields of pathways. Coactivation of two pathways that overlapped by 51-100% led to LTP; coactivation of pathways that overlapped by 0-50% did not. Moreover, LTD was induced in a crossed pathway when an ipsilateral pathway that overlapped by 51-100% was activated, but not when a nonoverlapping (0-50% overlap) ipsilateral pathway was activated. The degree of associative LTP or LTD that was induced in crossed pathways was correlated with the percent overlap with the terminal field of the active ipsilateral pathway. 5. Evaluation of whether LTD was induced when one division (medial or lateral) of the ipsilateral pathway was silent when the other division was conditioned revealed similar relationships.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Synaptic interface surface area increases with long-term potentiation in the hippocampal dentate gyrus.

The present study continues our attempt to understand the ultrastructural changes that accompany and may underlie long-term potentiation (LTP). This report describes changes with LTP in the surface area of the pre- and postsynaptic membrane apposition at the synapses formed by entorhinal cortical (EC) axons with granule cell dendritic spines of the dentate gyrus (DG). The electrophysiology and electron microscopy of the DGs from each animal followed conventional procedures. The trace length of the pre- and postsynaptic apposition was measured for identified asymmetric synapses in the dentate molecular layer. The total apposed membrane surface area per unit volume (Sv) was then computed for 4 categories of synaptic profiles for each third of the molecular layer. Statistical analysis of the Sv data used multivariate analyses of variance. Across the entire molecular layer, total apposed Sv does not change significantly with LTP. However, in the activated portion of the molecular layer, total apposed Sv increases significantly, reflecting a significant increase in the apposed Sv for the concave spine profiles there. For these spine profiles, the increased apposed Sv is due to the increased membrane area both at the postsynaptic density and beyond. The average apposed surface area per individual synapse also increases markedly with LTP. The present data support the hypothesis of coordinated pre- and postsynaptic anatomical changes with LTP in the EC-DG system.

Animals↗
PubMed1988

Evidence that associative interactions between synapses during the induction of long-term potentiation occur within local dendritic domains.

The present study evaluates whether the associative interactions between synapses that lead to long-term potentiation and depression (LTP and LTD) can occur between spatially segregated synapses of the medial and lateral temporodentate pathway of the rat. Coconditioning of crossed and ipsilateral pathways resulted in LTP of the crossed system only when the current sinks of the two conditioned pathways overlapped sufficiently. Likewise, conditioning of an ipsilateral pathway alone resulted in LTD of the crossed pathway only when those current sinks overlapped sufficiently. These observations support the idea that associative events that lead to LTP or LTD can be restricted to a local dendritic domain. The postsynaptic cell can therefore serve as more than one unit of integration for synaptic modification.

Animals↗
PubMed1986

Changes in the numerical density of synaptic contacts with long-term potentiation in the hippocampal dentate gyrus.

Long-term potentiation (LTP) in the rat dentate gyrus is a multifaceted phenomenon, including synaptic potentiation; simultaneous synaptic depression at neighboring, unconditioned synapses; and a change in the amount of cell firing produced by a specified amount of synaptic current (see Levy and Desmond: In G. Buzsaki and C. Vanderwolf (eds): Electrical Activity of The Archicortex. Budapest: Akademiai Kiado, pp. 359-373, '85b). This study presents long-term anatomical modifications that seem related to excitatory synaptic modification. These anatomical alterations appear early and persist for at least 60 minutes following conditioning stimulation. Each animal received test pulse stimulation delivered alternately to the angular bundles before and after brief, unilateral high-frequency conditioning stimulation that is typical of many LTP paradigms. Anatomical preparation followed standard procedures. Double-blind scoring procedures quantified the number of asymmetric synapses in the dentate molecular layer. These counts were converted to the number of synapses per unit volume using stereological corrections that combined geometrically derived theory and modest serial sectioning. Multivariate analysis of variance evaluated the statistical significance of changes in synapse density. Across all three groups of animals, conditioning stimulation does not significantly change the density of synaptic contacts across the entire molecular layer. There is a trend for a decreased density of synaptic contacts in the middle molecular layer, the region activated by the conditioning stimulation. Here the density of concave spine profiles increases significantly in all three groups of animals with conditioning stimulation. This increase accompanies significant decreases in the density of nonconcave, simple and ellipsoid, spine profiles. No significant changes in the density of shaft synapses occur with LTP-inducing conditioning stimulation. These data suggest that the concave spine profiles are a correlate of LTP-inducing stimulation and may be the potentiated synapses. We hypothesize that with synaptic potentiation there occurs an interconversion of spine synapses such that some nonconcave spine profiles become concave spine profiles. Such an interconversion apparently begins shortly after the conditioning stimulation and persists for at least 60 minutes.

Animals↗
PubMed1986

Changes in the postsynaptic density with long-term potentiation in the dentate gyrus.

The present study documents alterations in the size of the postsynaptic density (PSD) of synapses formed by entorhinal afferents with granule cell dendritic spines with long-term potentiation (LTP). These changes appear early and persist for at least 60 minutes after LTP-inducing conditioning stimulation. Each animal received test and conditioning stimulation typical of LTP paradigms. Electron microscopic preparation of the dentate gyri from each animal followed conventional procedures. PSD trace lengths of identified asymmetric synaptic profiles were measured. The total PSD length for four categories of synaptic profiles was determined for each third of the molecular layer. PSD surface area per unit volume of tissue (SV) was then computed from these data. Statistical analysis of the SV data used multivariate analysis of variance. PSD surface area per synapse was also estimated. Total PSD surface area per unit volume does not change significantly throughout the entire molecular layer with LTP-inducing conditioning stimulation. However, in the activated portion of the molecular layer, total PSD surface area per unit volume tends to increase with conditioning stimulation. In the middle third of the molecular layer, total PSD surface area per unit volume associated with the concave spine profiles increases significantly while there is a statistically significant decrease in total PSD SV associated with the nonconcave spine profiles. The PSD surface area per synapse also increases markedly. Since it seems that there is an interconversion of spine synapses from nonconcave to concave with LTP (Desmond and Levy: J. Comp. Neurol. In press, '86a), these data suggest that potentiated synapses have larger responses because, in part, they have larger neurotransmitter receptive regions.

Animals↗
PubMed1985

Granule cell dendritic spine density in the rat hippocampus varies with spine shape and location.

The number of granule cell dendritic spines per micrometer of dendritic length in the dorsal and ventral leaves of the dentate gyrus was quantified using light microscopic-Golgi preparations of normal adult rats. Spines were counted in terms of 3 categories of spine form for the 3 afferent termination zones of the molecular layer and corrected for shading errors. Total spine density averaged 1.6 spines/micron of dendritic length in the dorsal leaf and 1.3 spines/micron of dendritic length in the ventral leaf. Statistically significant differences in spine density existed among the 3 shape categories. Variations in spine density occurred by shape category among the afferent termination zones.

Animals↗
PubMed1984

Dendritic caliber and the 3/2 power relationship of dentate granule cells.

A quantitative examination of granule cell dendritic caliber and knowledge of dendritic lengths allows assessment of the distribution of dendritic membrane and the 3/2 power relationship at branch points. This paper presents caliber data of Golgi-impregnated rat dentate gyrus. We used camera lucida drawings of the dendritic trees of 15 dorsal leaf and 15 ventral leaf granule cells to quantify mean dendritic caliber, dendritic taper, the 3/2 power relationship of parent and sibling dendritic diameters at branch points, and surface area. First-order dendrites vary substantially in diameter. However, the mean caliber of all other dendrites is uniform across the proximal two-thirds of the molecular layer for the dorsal and ventral leaves. The average diameter here is 1 micron. More distally, only mean ventral leaf dendritic caliber declines. Granule cell dendritic taper is due primarily to caliber decreases at branch points and not to a gradual decline in diameter across the length of a dendritic segment. Comparing the parent segment diameter raised to the 3/2 power with the sum of the 3/2 powers of the two sibling segment diameters reveals, for the dendritic tree located within the distal two-thirds of the molecular layer, the desired 3/2 power relationship for the dorsal and ventral leaves. More proximally, where first-, second-, and third-order dendrites branch sequentially across a 60-100-micron extent, a 3/2 power relationship is not obtained. For the average dorsal leaf granule cell, dendritic surface area (without spines) is 11,984 micron2. The ratio of dendritic to somatic surface area is 28:1. Discussion of these data includes their implications for electrotonic modeling of the dentate granule cell.

Animals↗
PubMed1983

Synaptic correlates of associative potentiation/depression: an ultrastructural study in the hippocampus.

Brief high-frequency trains delivered to the monosynaptic entorhinal cortical input to the dentate gyrus result in both increases and decreases of synaptic strength as a function of whether a particular afferent is active during conditioning (associative potentiation/depression). The present report concerns the effect of such brief, high-frequency conditioning trains upon the asymmetric synapses of the rat dentate gyrus molecular layer. Only those animals whose responses increased at least 50% following conditioning stimulation were included in the study. Additional animals were used for one-dimensional current source density analyses to localize the activated synaptic region. Double blind scoring procedures were used to classify and quantify electron micrographic data. Asymmetric synapses were scored as a function of their position in the molecular layer, spine head size and shape, and postsynaptic density length. All data were treated as inherently matched comparisons between the conditioned and control sides of each animal. The number of large, concave spine synapses with large postsynaptic densities significantly increases in the central zone of synaptic activation. Bordering this zone are regions with increases in synaptic number following conditioning, primarily due to an increased number of small spine synapses. The increased number of large, concave spine synapses in the central zone is postulated to mediate associative potentiation. The many small spine heads just adjacent to the zone of strongest synaptic activation may reflect synaptic depression evoked at synapses inactive during conditioning.

Animals↗