scholarly journals Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-d-aspartate receptor activity in hippocampal CA3 circuits

2002 ◽  
Vol 158 (2) ◽  
pp. 215-220 ◽  
Author(s):  
Sayaka Ueno ◽  
Masako Tsukamoto ◽  
Tomoya Hirano ◽  
Kazuya Kikuchi ◽  
Maki K. Yamada ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Physiological Role ◽  
Chelating Agent ◽  
Stratum Radiatum ◽  
High Frequency Stimulation ◽  
Dependent Manner ◽  
Synaptic Terminals ◽  
Stratum Lucidum

Although Zn2+ is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2+ indicator ZnAF-2, the spatiotemporal dynamics of Zn2+ was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2+ was immediately elevated in the stratum lucidum, followed by a mild increase in the stratum radiatum adjacent to the stratum lucidum, but not in the distal area of stratum radiatum. The Zn2+ increase was insensitive to a non–N-methyl-d-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca2+-free medium, suggesting that Zn2+ is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring stratum radiatum. Electrophysiological analyses revealed that NMDA receptor–mediated synaptic responses in CA3 proximal stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn2+-chelating agent. Thus, Zn2+ serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experience-dependent non-Hebbian modulation of synaptic plasticity.

scholarly journals Imaging spatio-temporal patterns of long-term potentiation in mouse hippocampus

2003 ◽  
Vol 358 (1432) ◽  
pp. 689-693 ◽  
Author(s):  
Toshiyuki Hosokawa ◽  
Masaki Ohta ◽  
Takeshi Saito ◽  
Alan Fine
Keyword(s):  
Hippocampal Slices ◽  
Temporal Patterns ◽  
Long Term Potentiation ◽  
Optical Recording ◽  
Stratum Radiatum ◽  
High Frequency Stimulation ◽  
Optical Signals ◽  
Term Potentiation ◽  
Spatio Temporal

Spatio-temporal patterns of neuronal activity before and after the induction of long-term potentiation in mouse hippocampal slices were studied using a real-time high-resolution optical recording system. After staining the slices with voltage-sensitive dye, transmitted light images and extracellular field potentials were recorded in response to stimuli applied to CA1 stratum radiatum. Optical and electrical signals in response to single test pulses were enhanced for at least 30 minutes after brief high-frequency stimulation at the same site. In two-pathway experiments, potentiation was restricted to the tetanized pathway. The optical signals demonstrated that both the amplitude and area of the synaptic response were increased, in patterns not predictable from the initial, pretetanus, pattern of activation. Optical signals will be useful for investigating spatio-temporal patterns of synaptic enhancement underlying information storage in the brain.

scholarly journals LTD at mossy fiber synapses onto stratum lucidum interneurons requires TrkB and retrograde endocannabinoid signaling

2019 ◽  
Vol 121 (2) ◽  
pp. 609-619 ◽  
Author(s):  
Enhui Pan ◽  
Zirun Zhao ◽  
James O. McNamara
Keyword(s):  
High Frequency ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
High Frequency Stimulation ◽  
Long Term Depression ◽  
Stratum Lucidum ◽  
Frequency Stimulation ◽  
Retrograde Signal ◽  
Stimulation Of

Hippocampal mossy fiber axons simultaneously activate CA3 pyramidal cells and stratum lucidum interneurons (SLINs), the latter providing feedforward inhibition to control CA3 pyramidal cell excitability. Filopodial extensions of giant boutons of mossy fibers provide excitatory synaptic input to the SLIN. These filopodia undergo extraordinary structural plasticity causally linked to execution of memory tasks, leading us to seek the mechanisms by which activity regulates these synapses. High-frequency stimulation of the mossy fibers induces long-term depression (LTD) of their calcium-permeable AMPA receptor synapses with SLINs; previous work localized the site of induction to be postsynaptic and the site of expression to be presynaptic. Yet, the underlying signaling events and the identity of the retrograde signal are incompletely understood. We used whole cell recordings of SLINs in hippocampal slices from wild-type and mutant mice to explore the mechanisms. Genetic and pharmacologic perturbations revealed a requirement for both the receptor tyrosine kinase TrkB and its agonist, brain-derived neurotrophic factor (BDNF), for induction of LTD. Inclusion of inhibitors of Trk receptor kinase and PLC in the patch pipette prevented LTD. Endocannabinoid receptor antagonists and genetic deletion of the CB1 receptor prevented LTD. We propose a model whereby release of BDNF from mossy fiber filopodia activates TrkB and PLCγ1 signaling postsynaptically within SLINs, triggering synthesis and release of an endocannabinoid that serves as a retrograde signal, culminating in reduced glutamate release. Insights into the signaling pathways by which activity modifies function of these synapses will facilitate an understanding of their contribution to the local circuit and behavioral consequences of hippocampal granule cell activity. NEW & NOTEWORTHY We investigated signaling mechanisms underlying plasticity of the hippocampal mossy fiber filopodial synapse with interneurons in stratum lucidum. High-frequency stimulation of the mossy fibers induces long-term depression of this synapse. Our findings are consistent with a model in which brain-derived neurotrophic factor released from filopodia activates TrkB of a stratum lucidum interneuron; the ensuing activation of PLCγ1 induces synthesis of an endocannabinoid, which provides a retrograde signal leading to reduced release of glutamate presynaptically.

Delayed Signal Propagation via CA2 in Rat Hippocampal Slices Revealed by Optical Recording

1997 ◽  
Vol 78 (3) ◽  
pp. 1662-1668 ◽  
Author(s):  
Yuko Sekino ◽  
Kunihiko Obata ◽  
Manabu Tanifuji ◽  
Makoto Mizuno ◽  
Jin Murayama
Keyword(s):  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Mossy Fibers ◽  
Signal Propagation ◽  
Middle Part ◽  
Optical Recording ◽  
Stratum Radiatum ◽  
Ca1 Neurons ◽  
Optical Signals ◽  
Fiber Stimulation

Sekino, Yuko, Kunihiko Obata, Manabu Tanifuji, Makoto Mizuno, and Jin Murayama. Delayed signal propagation via CA2 in rat hippocampal slices revealed by optical recording. J. Neurophysiol. 78: 1662–1668, 1997. Signal propagation from mossy fibers to CA1 neurons was investigated in rat hippocampal slices by a combination of electrical and optical recordings. The slices were prepared by oblique sectioning of the middle part of the hippocampus to preserve fiber connections. The mossy fibers were stimulated to induce population spikes (PSs) and excitatory postsynaptic potentials in the middle part of the CA1 region. Latencies of maximal PSs in CA1 varied widely among slices; they ranged from 7 to 13.5 ms, with two maxima at 9 and 11.5 ms. The fastest PSs probably are evoked by the Schaffer collaterals that connect the CA3 and CA1 regions in the well-known trisynaptic circuit. However, the slower PSs suggest the existence of additional delayed inputs. To determine the source of the delayed input, slices were stained with a voltage-sensitive dye, RH482, and the optical signals relevant to membrane potential changes were detected by a high-resolution optical imaging system. Optical recording of responses to mossy fiber stimulation indicated two distinct types of signal propagation from CA3 to CA1. In preparations evincing the fast type of propagation, signals spread to CA1 within 7.2 ms after the mossy fiber stimulation. During such propagation, activity flowed directly from CA3 to the stratum radiatum of CA1. Other preparations illustrated slow signal propagation, in which optical signals were generated in CA2 before spreading to CA1. During such slow signal transmission, activity persisted in CA2 and its surrounding area for 3 ms before propagating to the strata radiatum and oriens in CA1. In such cases, CA1 activity was detected within 10.8 ms of mossy fiber stimulation. In some slices, a mixture of the fast and slow propagation patterns was observed, indicating that these two transmission modes can coexist. Our data reveal that CA2 neurons can transmit delayed excitatory signals to CA1 neurons. We therefore conclude that consideration of electrical signal propagation through the hippocampus should include flow through the CA2 region in addition to the traditional dentate gyrus–CA3–CA1 trisynaptic circuit.

Patterned Activity in Stratum Lacunosum Moleculare Inhibits CA1 Pyramidal Neuron Firing

1999 ◽  
Vol 82 (6) ◽  
pp. 3213-3222 ◽  
Author(s):  
Hannah Dvorak-Carbone ◽  
Erin M. Schuman
Keyword(s):  
Time Course ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
High Frequency Stimulation ◽  
Dependent Manner ◽  
Ca1 Pyramidal Cells ◽  
Frequency Stimulation ◽  
Primary Output ◽  
Ca1 Pyramidal Neuron ◽  
Stratum Lacunosum Moleculare

CA1 pyramidal cells are the primary output neurons of the hippocampus, carrying information about the result of hippocampal network processing to the subiculum and entorhinal cortex (EC) and thence out to the rest of the brain. The primary excitatory drive to the CA1 pyramidal cells comes via the Schaffer collateral (SC) projection from area CA3. There is also a direct projection from EC to stratum lacunosum-moleculare (SLM) of CA1, an input well positioned to modulate information flow through the hippocampus. High-frequency stimulation in SLM evokes an inhibition sufficiently strong to prevent CA1 pyramidal cells from spiking in response to SC input, a phenomenon we refer to as spike-blocking. We characterized the spike-blocking efficacy of burst stimulation (10 stimuli at 100 Hz) in SLM and found that it is greatest at ∼300–600 ms after the burst, consistent with the time course of the slow GABABsignaling pathway. Spike-blocking efficacy increases in potency with the number of SLM stimuli in a burst, but also decreases with repeated presentations of SLM bursts. Spike-blocking was eliminated in the presence of GABABantagonists. We have identified a candidate population of interneurons in SLM and distal stratum radiatum (SR) that may mediate this spike-blocking effect. We conclude that the output of CA1 pyramidal cells, and hence the hippocampus, is modulated in an input pattern-dependent manner by activation of the direct pathway from EC.

Picrotoxin-induced epileptiform activity in hippocampus: role of endogenous versus synaptic factors

1984 ◽  
Vol 51 (5) ◽  
pp. 1011-1027 ◽  
Author(s):  
J. J. Hablitz
Keyword(s):  
Refractory Period ◽  
Mossy Fiber ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Extracellular Recording ◽  
Synaptic Activity ◽  
Stratum Radiatum ◽  
Resting Membrane Potential ◽  
Stimulation Of

Picrotoxin-(PTX) induced epileptiform activity was studied in guinea pig hippocampal slices maintained in vitro, using intra- and extracellular recording techniques. The observed pattern of spontaneous and evoked epileptiform activity was quite complex. Spontaneous epileptiform events originated in the CA3 region and subsequently spread or propagated to CA1. Activation of CA1 could then reactivate CA3. This reverberation of activity was seen also following stimulation of the mossy fiber afferents from the dentate gyrus to CA3. Stimulation of fibers in the stratum radiatum of the CA1 region could trigger, at short latency, epileptiform activity that either was localized in CA1 or also occurred in CA3, with a late secondary discharge in CA1. This is attributed to a backfiring of the Schaffer collaterals and illustrates the ability of a variety of CA3 inputs to trigger epileptiform activity. Bath-applied PTX, at concentrations of 50-200 microM, had no apparent effect on the resting membrane potential or input resistance of the CA3 cells tested. Depolarizing current pulses elicited characteristic endogenous-burst responses that were not altered by PTX. Synaptic activity evoked by mossy fiber stimulation was altered markedly by PTX. The pattern of observed changes indicated that PTX reduced inhibitory postsynaptic potential (IPSP) amplitudes, resulting in the appearance of repetitive (presumably recurrent) excitatory inputs. Paroxysmal depolarizing shifts ( PDSs ) were generated by the coalescence of these excitatory inputs. Two types of spontaneous bursting were observed after PTX application. The first type was nonepileptiform , all or none in nature, and its frequency was voltage dependent. The second type of spontaneous burst was the PDS. It was epileptiform in character because it was associated with the synchronous discharge of many neurons. It was graded in nature, and its frequency was voltage independent. The graded nature of the PDS was demonstrated by varying the duration and intensity of the orthodromic stimulation. Trains of stimulation could produce PDSs that lasted 500-800 ms. A refractory period was observed following a PDS. By varying the strength of the orthodromic stimulation, it was possible to demonstrate that for the intervals tested this was a relative, not absolute, refractory period. Intracellular recordings in CA3 neurons indicated that each spontaneous PDS was followed by an afterhyperpolarization (AHP).

scholarly journals IL-33 Acts to Express Schaffer Collateral/CA1 LTP and Regulate Learning and Memory by Targeting MyD88

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Tomoyuki Nishizaki
Keyword(s):  
Learning And Memory ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Spatial Learning And Memory ◽  
Dependent Manner ◽  
Wild Type ◽  
Schaffer Collateral ◽  
Deficient Mice ◽  
Wild Type Control

Interleukin-33 (IL-33) is recognized to transmit a signal through a heterodimeric receptor complex ST2/interleukin-1 receptor accessory protein (IL-1RAcP) bearing activation of myeloid differentiation factor 88 (MyD88). High-frequency stimulation to the Schaffer collateral induced long-term potentiation (LTP) in the CA1 region of hippocampal slices from wild-type control mice. Schaffer collateral/CA1 LTP in IL-33-deficient mice was significantly suppressed, which was neutralized by application with IL-33. Similar suppression of the LTP was found with MyD88-deficient mice but not with ST2-deficient mice. In the water maze test, the acquisition latency in IL-33-deficient and MyD88-deficient mice was significantly prolonged as compared with that in wild-type control mice. Moreover, the retention latency in MyD88-deficient mice was markedly prolonged. In contrast, the acquisition and retention latencies in ST2-deficient mice were not affected. Taken together, these results show that IL-33 acts to express Schaffer collateral/CA1 LTP relevant to spatial learning and memory in a MyD88-dependent manner and that the LTP might be expressed through an IL-1R1/IL-1RAcP-MyD88 pathway in the absence of ST2.

scholarly journals Activity-dependent differences in function between proximal and distal Schaffer collaterals

2015 ◽  
Vol 113 (10) ◽  
pp. 3646-3662 ◽  
Author(s):  
Benjamin Owen ◽  
Lawrence M. Grover
Keyword(s):  
High Frequency ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
High Frequency Stimulation ◽  
Burst Stimulation ◽  
Schaffer Collateral ◽  
Whole Cell ◽  
Schaffer Collaterals

Axon conduction fidelity is important for signal transmission and has been studied in various axons, including the Schaffer collateral axons of the hippocampus. Previously, we reported that high-frequency stimulation (HFS) depresses Schaffer collateral excitability when assessed by whole-cell recordings from CA3 pyramidal cells but induces biphasic excitability changes (increase followed by decrease) in extracellular recordings of CA1 fiber volleys. Here, we examined responses from proximal (whole-cell or field-potential recordings from CA3 pyramidal cell somata) and distal (field-potential recordings from CA1 stratum radiatum) portions of the Schaffer collaterals during HFS and burst stimulation in hippocampal slices. Whole-cell and dual-field-potential recordings using 10–100-Hz HFS revealed frequency-dependent changes like those previously described, with higher frequencies producing more drastic changes. Dual-field-potential recordings revealed substantial differences in the response to HFS between proximal and distal regions of the Schaffer collaterals, with proximal axons depressing more strongly and only distal axons showing an initial excitability increase. Because CA3 pyramidal neurons normally fire in short bursts rather than long high-frequency trains, we repeated the dual recordings using 100–1,000-ms interval burst stimulation. Burst stimulation produced changes similar to those during HFS, with shorter intervals causing more drastic changes and substantial differences observed between proximal and distal axons. We suggest that functional differences between proximal and distal Schaffer collaterals may allow selective filtering of nonphysiological activity while maximizing successful conduction of physiological activity throughout an extensive axonal arbor.

scholarly journals Retrograde suppression of post-tetanic potentiation at the mossy fiber-CA3 pyramidal cell synapse

2020 ◽  
Author(s):  
Sachin Makani ◽  
Stefano Lutzu ◽  
Pablo J. Lituma ◽  
David L. Hunt ◽  
Pablo E. Castillo
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Dependent Manner ◽  
Short Term ◽  
Short Term Plasticity ◽  
Dentate Granule Cells ◽  
Post Tetanic Potentiation ◽  
Frequency Facilitation

ABSTRACTIn the hippocampus, the excitatory synapse between dentate granule cell axons – or mossy fibers (MF) – and CA3 pyramidal cells (MF-CA3) expresses robust forms of short-term plasticity, such as frequency facilitation and post-tetanic potentiation (PTP). These forms of plasticity are due to increases in neurotransmitter release, and can be engaged when dentate granule cells fire in bursts (e.g. during exploratory behaviors) and bring CA3 pyramidal neurons above threshold. While frequency facilitation at this synapse is limited by endogenous activation of presynaptic metabotropic glutamate receptors, whether MF-PTP can be regulated in an activity-dependent manner is unknown. Here, using physiologically relevant patterns of mossy fiber stimulation in acute mouse hippocampal slices, we found that disrupting postsynaptic Ca2+ dynamics increases MF-PTP, strongly suggesting a form of Ca2+-dependent retrograde suppression of this form of plasticity. PTP suppression requires a few seconds of MF bursting activity and Ca2+ release from internal stores. Our findings raise the possibility that the powerful MF-CA3 synapse can negatively regulate its own strength not only during PTP-inducing activity typical of normal exploratory behaviors, but also during epileptic activity.SIGNIFICANCE STATEMENTThe powerful mossy fiber-CA3 synapse exhibits strong forms of plasticity that are engaged during location-specific exploration, when dentate granule cells fire in bursts. While this synapse is well-known for its presynaptically-expressed LTP and LTD, much less is known about the robust changes that occur on a shorter time scale. How such short-term plasticity is regulated, in particular, remains poorly understood. Unexpectedly, an in vivo-like pattern of presynaptic activity induced robust post-tetanic potentiation (PTP) only when the postsynaptic cell was loaded with a high concentration of Ca2+ buffer, indicating a form of Ca2+–dependent retrograde suppression of PTP. Such suppression may have profound implications for how environmental cues are encoded into neural assemblies, and for limiting network hyperexcitability during seizures.

Synaptic Activation of GABAA Receptors Induces Neuronal Uptake of Ca2+ in Adult Rat Hippocampal Slices

1999 ◽  
Vol 81 (2) ◽  
pp. 811-816 ◽  
Author(s):  
Anna-Maija Autere ◽  
Karri Lamsa ◽  
Kai Kaila ◽  
Tomi Taira
Keyword(s):  
Glutamate Receptor ◽  
Hippocampal Slices ◽  
Underlying Mechanism ◽  
Adult Brain ◽  
Stratum Radiatum ◽  
Neuronal Uptake ◽  
High Frequency Stimulation ◽  
Synaptic Activation ◽  
Adult Rat ◽  
Ethanesulfonic Acid

Synaptic activation of GABAA receptors induces neuronal uptake of Ca2+ in adult rat hippocampal slices. Synaptically evoked transmembrane movements of Ca2+ in the adult CNS have almost exclusively been attributed to activation of glutamate receptor channels and the consequent triggering of voltage-gated calcium channels (VGCCs). Using microelectrodes for measuring free extracellular Ca2+([Ca2+]o) and extracellular space (ECS) volume, we show here for the first time that synaptic stimulation of γ-aminobutyric acid-A (GABAA) receptors can result in a decrease in [Ca2+]o in adult rat hippocampal slices. High-frequency stimulation (100–200 Hz, 0.4–0.5 s) applied in stratum radiatum close (≤0.5 mm) to the recording site induced a 0.1- to 0.3-mM transient fall in [Ca2+]o from a baseline level of 1.6 mM. Concomitantly, a 30–40% decrease in the ECS volume was seen. Exposure of drug-naı̈ve slices to the GABAA receptor antagonist picrotoxin (100 μM) first attenuated and only thereafter augmented the Ca2+ shifts. Application of ionotropic glutamate receptor antagonists resulted in a monotonic reduction of the Ca2+ response, but a large Ca2+ shift persisted (60–70% of the original), which was attenuated by a subsequent application of picrotoxin or bicuculline. In the absence of ionotropic glutamatergic transmission, pentobarbital sodium (100 μM), an up-modulator of the GABAA receptor, strongly enhanced the activity-evoked changes in [Ca2+]o. We suggest that the underlying mechanism of GABA-induced Ca2+ transients is the activation of VGCCs by bicarbonate-dependent GABA-mediated depolarizing postsynaptic potentials. Accordingly, stimulation-evoked Ca2+ shifts were inhibited by the membrane-permeant inhibitor of carbonic anhydrase, ethoxyzolamide (50 μM) or in N-2-hydroxyethylpiperazine- N′-2-ethanesulfonic acid (HEPES)–buffered HCO3-free solution. Neuronal Ca2+ uptake caused by intense synaptic activation of GABAA receptors may prove to be an important mechanism in the modulation of activity-dependent neuronal plasticity, epileptogenesis, and cell survival in the adult brain.

Endogenous pH Shifts Facilitate Spreading Depression by Effect on NMDA Receptors

1999 ◽  
Vol 81 (4) ◽  
pp. 1988-1991 ◽  
Author(s):  
C. K. Tong ◽  
M. Chesler
Keyword(s):  
Nmda Receptor ◽  
Carbonic Anhydrase ◽  
Nmda Receptors ◽  
Spreading Depression ◽  
Hippocampal Slices ◽  
Nmda Receptor Antagonist ◽  
Ringer Solution ◽  
Stratum Radiatum ◽  
Alkaline Shift ◽  
Potential Electrode

Endogenous pH shifts facilitate spreading depression by effect on NMDA receptors. Rapid extracellular alkalinizations accompany normal neuronal activity and have been implicated in the modulation of N-methyl-d-aspartate (NMDA) receptors. Particularly large alkaline transients also occur at the onset of spreading depression (SD). To test whether these endogenous pH shifts can modulate SD, the alkaline shift was amplified using benzolamide, a poorly permeant inhibitor of interstitial carbonic anhydrase. SD was evoked by microinjection of 1.2 M KCl into the CA1 stratum radiatum of rat hippocampal slices and recorded by a proximal double-barreled pH microelectrode and a distal potential electrode. In Ringer solution of pH 7.1 containing picrotoxin (but not at a bath pH of 7.4), addition of 10 μM benzolamide increased the SD alkaline shift from 0.20 ± 0.07 to 0.38 ± 0.17 unit pH (means ± SE). This was correlated with a significant shortening of the latency and an increase in the conduction velocity by 26 ± 16%. In the presence of the NMDA receptor antagonist dl−2-amino-5-phosphonovaleric acid (APV), benzolamide still amplified the alkaline transient, however, its effect on the SD latency and propagation velocity was abolished. The intrinsic modulation of SD by its alkaline transient may play an important role under focal ischemic conditions by removing the proton block of NMDA receptors where interstitial acidosis would otherwise limit NMDA receptor activity.

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