scholarly journals Coincident Glutamatergic and Cholinergic Inputs Transiently Depress Glutamate Release at Rat Schaffer Collateral Synapses

2007 ◽  
Vol 97 (6) ◽  
pp. 4108-4119 ◽  
Author(s):  
Keith E. Gipson ◽  
Mark F. Yeckel
Keyword(s):  
Acetylcholine Receptors ◽  
Glutamate Release ◽  
Acetylcholinesterase Inhibitor ◽  
Hippocampal Slices ◽  
Medial Septum ◽  
Network Activity ◽  
Stratum Radiatum ◽  
Hippocampal Function ◽  
Schaffer Collateral ◽  
Single Receptor

The mammalian hippocampus, together with subcortical and cortical areas, is responsible for some forms of learning and memory. Proper hippocampal function depends on the highly dynamic nature of its circuitry, including the ability of synapses to change their strength for brief to long periods of time. In this study, we focused on a transient depression of glutamatergic synaptic transmission at Schaffer collateral synapses in acute hippocampal slices. The depression of evoked excitatory postsynaptic current (EPSC) amplitudes, herein called transient depression, follows brief trains of synaptic stimulation in stratum radiatum of CA1 and lasts for 2–3 min. Depression results from a decrease in presynaptic glutamate release, as NMDA-receptor–mediated EPSCs and composite EPSCs are depressed similarly and depression is accompanied by an increase in the paired-pulse ratio. Transient depression is prevented by blockade of metabotropic glutamate and acetylcholine receptors, presumably located presynaptically. These two receptor types—acting together—cause depression. Blockade of a single receptor type necessitates significantly stronger conditioning trains for triggering depression. Addition of an acetylcholinesterase inhibitor enables depression from previously insufficient conditioning trains. Furthermore, a strong coincident, but not causal, relationship existed between presynaptic depression and postsynaptic internal Ca2+ release, emphasizing the potential importance of functional interactions between presynaptic and postsynaptic effects of convergent cholinergic and glutamatergic inputs to CA1. These convergent afferents, one intrinsic to the hippocampus and the other likely originating in the medial septum, may regulate CA1 network activity, the induction of long-term synaptic plasticity, and ultimately hippocampal function.

scholarly journals In Vivo Plasticity at Hippocampal Schaffer Collateral-CA1 Synapses: Replicability of the LTP Response and Pharmacology in the Long-Evans Rat

2020 ◽  
Vol 2020 ◽  
pp. 1-24
Author(s):  
A. Ahnaou ◽  
E. White ◽  
R. Biermans ◽  
N. V. Manyakov ◽  
W. H. I. M. Drinkenburg
Keyword(s):  
Synaptic Plasticity ◽  
Acetylcholinesterase Inhibitor ◽  
Nmda Antagonist ◽  
Long Term Potentiation ◽  
Stratum Radiatum ◽  
High Frequency Stimulation ◽  
Schaffer Collateral ◽  
Maximum Slope ◽  
Cognitive Studies ◽  
Long Evans

Broad issues associated with non-replicability have been described in experimental pharmacological and behavioral cognitive studies. Efforts to prevent biases that contribute to non-replicable scientific protocols and to improve experimental rigor for reproducibility are increasingly seen as a basic requirement for the integrity of scientific research. Synaptic plasticity, encompassing long-term potentiation (LTP), is believed to underlie mechanisms of learning and memory. The present study was undertaken in Long-Evans (LE) rats, a strain of rat commonly used in cognitive behavioral tests, to (1) compare three LTP tetanisation protocols, namely, the high-frequency stimulation (HFS), the theta-burst stimulation (TBS), and the paired-pulse facilitation (PPF) at the Schaffer collateral-CA1 stratum radiatum synapse and to (2) assess sensitivity to acute pharmacology. Results: (1) When compared to Sprague-Dawley (SD) rats, the HFS using a stimulus intensity of 50% of the maximum slope obtained from input/output (I/O) curves elicited lower and higher thresholds of synaptic plasticity responses in SD and LE rats, respectively. The 2-train TBS protocol significantly enhanced the LTP response in LE rats over the 5- and 10-train TBS protocols in both strains, and the 5 × TBS protocol inducing a subthreshold LTP response was used in subsequent pharmacological studies in LE rats. The PPF protocol, investigating the locus of the LTP response, showed no difference for the selected interstimulus intervals. (2) Scopolamine, a nonspecific muscarinic antagonist, had a subtle effect, whereas donepezil, an acetylcholinesterase inhibitor, significantly enhanced the LTP response, demonstrating the sensitivity of the TBS protocol to enhanced cholinergic tone. MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, significantly reduced LTP response, while memantine, another NMDA antagonist, had no effect on LTP response, likely associated with a weaker TBS protocol. PQ10, a phosphodiesterase-10 inhibitor, significantly enhanced the TBS-induced LTP response, but did not change the PPF response. Overall, the results confirm the strain-dependent differences in the form of synaptic plasticity, replicate earlier plasticity results, and report effective protocols that generate a relatively subthreshold margin of LTP induction and maintenance, which are suitable for pharmacology in the LE rat strain mainly used in cognitive studies.

Abstract TP281: Increased Susceptibility to Excitotoxic Injury in Rat Hippocampal Slices Exposed to Intermittent Hypoxia

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Rekha Jagadapillai ◽  
Nicholas Mellen ◽  
Leroy R Sachleben ◽  
Evelyne Gozal
Keyword(s):  
Intermittent Hypoxia ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Optical Recording ◽  
Network Activity ◽  
Viable Cells ◽  
High K ◽  
Obstructive Sleep ◽  
Increased Risk ◽  
Glutamate Homeostasis

Introduction: The effect of sustained hypoxia (SH) on brain metabolism has been well studied. However less is known about intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), associated with increased risk for stroke, outcome severity and functional consequences. Hypothesis: Impaired glutamate homeostasis after IH may underlie increased brain vulnerability to stroke-induced excitotoxicity. Methods: P4 organotypic rat hippocampal slices cultured for 7 days, were exposed for 7 additional days to IH (alternating 2 min 5% O2 - 15 min 21% O2), SH (5% O2) or normoxia (RA; 21% O2), followed by 3 glutamate challenges (first and last 200 μM, 15 min, emulating a physiological stimulus; second, 10 mM, 10 min, emulating stroke-induced excitotoxicity). Viability was assessed by propidium iodide (PI) uptake at baseline then after each glutamate challenge to assess whether hypoxia impairs the response to physiological or excitotoxic glutamate release. Glial GFAP, neuronal MAP2, EAAT1 and EAAT2 glutamate transporters expression was assessed by immunohistochemistry. Spontaneous and evoked Ca2+ transient activity was assessed in Fluo-8LTM AM loaded slices, by optical recording of Ca2+ spikes proximal to a bipolar stimulating electrode, before and after each of 3 single 2 ms stimuli (0.6 mA). Ca2+ transients after high K+ were used to determine the total number of viable cells. Results: Viability, GFAP, MAP2, EAAT1 and EAAT2 expression and basal Ca2+ spikes activity significantly decreased in IH. The number of neurons with spikes evoked within 500 ms of stimuli was not significantly different, but RA evoked responses were more tightly clustered. Residual network activity, assessed by number of neurons with spikes 500 ms post stimulus, was significantly different RA>SH>IH. Overall number of spiking cells after high K+, representing total viable cells, confirmed the viability data obtained with PI staining. Conclusions: IH is more detrimental to cell survival and glutamate homeostasis than SH, suggesting that in addition to vascular changes, impaired glutamate homeostasis may increase OSA patients’ susceptibility to ischemic events.

scholarly journals M1 and M4 Receptors Modulate Hippocampal Pyramidal Neurons

2011 ◽  
Vol 105 (2) ◽  
pp. 779-792 ◽  
Author(s):  
Sameera Dasari ◽  
Allan T. Gulledge
Keyword(s):  
Pyramidal Neuron ◽  
Pyramidal Neurons ◽  
Glutamate Release ◽  
Stratum Radiatum ◽  
Cholinergic Modulation ◽  
Schaffer Collateral ◽  
Hippocampal Pyramidal Neurons ◽  
Ca1 Neurons ◽  
Neuron Excitability ◽  
M1 Receptors

Acetylcholine (ACh), acting at muscarinic ACh receptors (mAChRs), modulates the excitability and synaptic connectivity of hippocampal pyramidal neurons. CA1 pyramidal neurons respond to transient (“phasic”) mAChR activation with biphasic responses in which inhibition is followed by excitation, whereas prolonged (“tonic”) mAChR activation increases CA1 neuron excitability. Both phasic and tonic mAChR activation excites pyramidal neurons in the CA3 region, yet ACh suppresses glutamate release at the CA3-to-CA1 synapse (the Schaffer–collateral pathway). Using mice genetically lacking specific mAChRs (mAChR knockout mice), we identified the mAChR subtypes responsible for cholinergic modulation of hippocampal pyramidal neuron excitability and synaptic transmission. Knockout of M1 receptors significantly reduced, or eliminated, most phasic and tonic cholinergic responses in CA1 and CA3 pyramidal neurons. On the other hand, in the absence of other Gq-linked mAChRs (M3 and M5), M1 receptors proved sufficient for all postsynaptic cholinergic effects on CA1 and CA3 pyramidal neuron excitability. M3 receptors were able to participate in tonic depolarization of CA1 neurons, but otherwise contributed little to cholinergic responses. At the Schaffer–collateral synapse, bath application of the cholinergic agonist carbachol suppressed stratum radiatum–evoked excitatory postsynaptic potentials (EPSPs) in wild-type CA1 neurons and in CA1 neurons from mice lacking M1 or M2 receptors. However, Schaffer–collateral EPSPs were not significantly suppressed by carbachol in neurons lacking M4 receptors. We therefore conclude that M1 and M4 receptors are the major mAChR subtypes responsible for direct cholinergic modulation of the excitatory hippocampal circuit.

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 Release probability increases towards distal dendrites boosting high-frequency signal transfer in the rodent hippocampus

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Thomas P Jensen ◽  
Olga Kopach ◽  
James P Reynolds ◽  
Leonid P Savtchenko ◽  
Dmitri A Rusakov
Keyword(s):  
High Frequency ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Network Activity ◽  
Signal Transfer ◽  
High Frequency Signal ◽  
Release Probability ◽  
Acute Hippocampal Slices ◽  
Rats And Mice ◽  
Trace Formation

Dendritic integration of synaptic inputs involves their increased electrotonic attenuation at distal dendrites, which can be counterbalanced by the increased synaptic receptor density. However, during network activity, the influence of individual synapses depends on their release fidelity, the dendritic distribution of which remains poorly understood. Here, we employed classical optical quantal analyses and a genetically encoded optical glutamate sensor in acute hippocampal slices of rats and mice to monitor glutamate release at CA3-CA1 synapses. We find that their release probability increases with greater distances from the soma. Similar-fidelity synapses tend to group together, whereas release probability shows no trends regarding the branch ends. Simulations with a realistic CA1 pyramidal cell hosting stochastic synapses suggest that the observed trends boost signal transfer fidelity, particularly at higher input frequencies. Because high-frequency bursting has been associated with learning, the release probability pattern we have found may play a key role in memory trace formation.

scholarly journals An acetylcholinesterase inhibitor, eserine, induces long-term depression at CA3-CA1 synapses in the hippocampus of adult rats

2014 ◽  
Vol 112 (10) ◽  
pp. 2388-2397 ◽  
Author(s):  
Robert Alan Mans ◽  
Brian A. Warmus ◽  
Caroline C. Smith ◽  
Lori L. McMahon
Keyword(s):  
Glutamate Release ◽  
Acetylcholinesterase Inhibitor ◽  
Hippocampal Slices ◽  
Cholinergic Innervation ◽  
Ache Inhibition ◽  
Long Term Depression ◽  
Adult Rats ◽  
Pharmacological Inhibition ◽  
Ache Inhibitors

Studies in humans and rodents support a role for muscarinic ACh receptor (mAChR) and nicotinic AChR in learning and memory, and both regulate hippocampal synaptic plasticity using complex and often times opposing mechanisms. Acetylcholinesterase (AChE) inhibitors are commonly prescribed to enhance cholinergic signaling in Alzheimer's disease in hopes of rescuing cognitive function, caused, in part, by degeneration of cholinergic innervation to the hippocampus and cortex. Unfortunately, therapeutic efficacy is moderate and inconsistent, perhaps due to unanticipated mechanisms. M1 mAChRs bidirectionally control synaptic strength at CA3-CA1 synapses; weak pharmacological activation using carbachol (CCh) facilitates potentiation, whereas strong agonism induces muscarinic long-term depression (mLTD) via an ERK-dependent mechanism. Here, we tested the prediction that accumulation of extracellular ACh via inhibition of AChE is sufficient to induce LTD at CA3-CA1 synapses in hippocampal slices from adult rats. Although AChE inhibition with eserine induces LTD, it unexpectedly does not share properties with mLTD induced by CCh, as reported previously. Eserine-LTD was prevented by the M3 mAChR-preferring antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), and pharmacological inhibition of MEK was completely ineffective. Additionally, pharmacological inhibition of p38 MAPK prevents mLTD but has no effect on eserine-LTD. Finally, long-term expression of eserine-LTD is partially dependent on a decrease in presynaptic release probability, likely caused by tonic activation of mAChRs by the sustained increase in extracellular ACh. Thus these findings extend current literature by showing that pharmacological AChE inhibition causes a prolonged decrease in presynaptic glutamate release at CA3-CA1 synapses, in addition to inducing a likely postsynaptic form of LTD.

Desynchronization of Glutamate Release Prolongs Synchronous CA3 Network Activity

2007 ◽  
Vol 97 (5) ◽  
pp. 3812-3818 ◽  
Author(s):  
Jethro Jones ◽  
Elizabeth A. Stubblefield ◽  
Timothy A. Benke ◽  
Kevin J. Staley
Keyword(s):  
Glutamate Release ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Neural Population ◽  
Axon Terminals ◽  
Rate Of Spread ◽  
Hippocampal Ca3 ◽  
Recurrent Collateral

Periodic bursts of activity in the disinhibited in vitro hippocampal CA3 network spread through the neural population by the glutamatergic recurrent collateral axons that link CA3 pyramidal cells. It was previously proposed that these bursts of activity are terminated by exhaustion of releasable glutamate at the recurrent collateral synapses so that the next periodic burst of network activity cannot occur until the supply of glutamate has been replenished. As a test of this hypothesis, the rate of glutamate release at CA3 axon terminals was reduced by substitution of extracellular Ca2+ with Sr2+. Reduction of the rate of glutamate release reduces the rate of depletion and should thereby prolong bursts. Here we demonstrate that Sr2+ substitution prolongs spontaneous bursts in the disinhibited adult CA3 hippocampal slices to 37.2 ± 7.6 (SE) times the duration in control conditions. Sr2+ also decreased the probability of burst initiation and the rate of burst onset, consistent with reduced synchrony of glutamate release and a consequent reduced rate of spread of excitation through the slice. These findings support the supply of releasable glutamate as an important determinant of the probability and duration of synchronous CA3 network activity.

scholarly journals Early detonation by sprouted mossy fibers enables aberrant dentate network activity

2019 ◽  
Vol 116 (22) ◽  
pp. 10994-10999
Author(s):  
William D. Hendricks ◽  
Gary L. Westbrook ◽  
Eric Schnell
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Mossy Fibers ◽  
Network Activity ◽  
Dentate Granule Cell ◽  
Action Potential Firing ◽  
Light Pulses ◽  
The Impact

In temporal lobe epilepsy, sprouting of hippocampal mossy fiber axons onto dentate granule cell dendrites creates a recurrent excitatory network. However, unlike mossy fibers projecting to CA3, sprouted mossy fiber synapses depress upon repetitive activation. Thus, despite their proximal location, relatively large presynaptic terminals, and ability to excite target neurons, the impact of sprouted mossy fiber synapses on hippocampal hyperexcitability is unclear. We find that despite their short-term depression, single episodes of sprouted mossy fiber activation in hippocampal slices initiated bursts of recurrent polysynaptic excitation. Consistent with a contribution to network hyperexcitability, optogenetic activation of sprouted mossy fibers reliably triggered action potential firing in postsynaptic dentate granule cells after single light pulses. This pattern resulted in a shift in network recruitment dynamics to an “early detonation” mode and an increased probability of release compared with mossy fiber synapses in CA3. A lack of tonic adenosine-mediated inhibition contributed to the higher probability of glutamate release, thus facilitating reverberant circuit activity.

scholarly journals Mecamylamine modulates epileptiform discharges in low-Mg2+ model of epilepsy

2021 ◽  
Vol 67 (1) ◽  
pp. 11-15
Author(s):  
O.S. Zapukhliak ◽  
◽  
D.S. Isaev ◽  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Brain Slices ◽  
Network Activity ◽  
Therapeutic Effects ◽  
Nicotinic Acetylcholine ◽  
Beneficial Effects ◽  
Epileptiform Discharges

Mecamylamine is a nonselective antagonist of nicotinic acetylcholine receptors that was developed as an antihypertensive medication and is now being studied for its beneficial effects in several pathological conditions, such as substance abuse, depression, anxiety and epilepsy. In this work, we investigate the effect of mecamylamine on the manifestations of seizure-like activity evoked by perfusion of hippocampal slices with low-Mg2+ solution of artificial cerebrospinal fluid. Reducing Mg2+ concentration in extracellular solution induced two distinct types of epileptiform activity: recurring seizure-like activity and continuous discharges. Application of mecamylamine significantly increased internal frequency of recurring seizurelike activity and significantly decreased inter-event intervals between continuous discharges. We also show that mecamylamine significantly decreased internal frequency of continuous epileptiform discharges. The results of our work show that mecamylamine exerts modulatory effect on the low-Mg2+ epileptiform activity induced in hippocampal acute rat brain slices. Additionally, obtained results indicate the role of nicotinic acetylcholine receptors in the modulation of hippocampal network activity, which might explain some of the therapeutic effects of mecamylamine in CNS.

Aluminum Suppresses Effect of Nicotine on Gamma Oscillations (20-40 Hz) in Mouse Hippocampal Slices

2018 ◽  
Vol 17 (6) ◽  
pp. 404-411 ◽  
Author(s):  
Syeda Mehpara Farhat ◽  
Touqeer Ahmed
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Peak Power ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Facilitatory Effect

Background: Aluminum (Al) causes neurodegeneration and its toxic effects on cholinergic system in the brain is well documented. However, it is unknown whether and how Al changes oscillation patterns, driven by the cholinergic system, in the hippocampus. Objective: We studied acute effects of Al on nicotinic acetylcholine receptors (nAChRs)-mediated modulation of persistent gamma oscillations in the hippocampus. Method: The field potential recording was done in CA3 area of acute hippocampal slices. Results: Carbachol-induced gamma oscillation peak power increased (1.32±0.09mV2/Hz, P<0.01) in control conditions (without Al) by application of 10µM nicotine as compared to baseline value normalized to 1. This nicotine-induced facilitation of gamma oscillation peak power was found to depend on non-α7 nAChRs. In slices with Al pre-incubation for three to four hours, gamma oscillation peak power was reduced (5.4±1.8mV2/Hz, P<0.05) and facilitatory effect of nicotine on gamma oscillation peak power was blocked as compared to the control (18.06±2.1mV2/Hz) or one hour Al pre-incubated slices (11.3±2.5mV2/Hz). Intriguingly wash-out, after three to four hours of Al incubation, failed to restore baseline oscillation power and its facilitation by nicotine as no difference was observed in gamma oscillation peak power between Al wash-out slices (3.4±1.1mV2/Hz) and slices without washout (3.6±0.9mV2/Hz). Conclusion: This study shows that at cellular level, exposure of hippocampal tissue to Al compromised nAChR-mediated facilitation of cholinergic hippocampal gamma oscillations. Longer in vitro Al exposure caused permanent changes in hippocampal oscillogenic circuitry and changed its sensitivity to nAChR-modulation. This study will help to understand the possible mechanism of cognitive decline induced by Al.

Sign in / Sign up

Export Citation Format

Share Document