scholarly journals Acetylcholine disinhibits hippocampal circuits to enable rapid formation of overlapping memory ensembles

2017 ◽  
Author(s):  
Luke Y. Prince ◽  
Krasimira Tsaneva-Atanasova ◽  
Claudia Clopath ◽  
Jack R. Mellor
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Cholinergic Receptor ◽  
Receptor Activation ◽  
Cellular Excitability ◽  
Rapid Formation ◽  
Ca3 Pyramidal Cells ◽  
Episodic Memories ◽  
Spiking Neural Network Model

AbstractIn the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. Acetylcholine is proposed as the salient signal that determines which memories are encoded but its actions on mossy fiber transmission are largely unknown. Here, we show experimentally that cholinergic receptor activation suppresses feedforward inhibition and enhances excitatory-inhibitory ratio. In reconstructions of CA3 pyramidal cells, this disinhibition enables postsynaptic dendritic depolarization required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how a combination of disinhibited mossy fiber activity, enhanced cellular excitability and reduced recurrent synapse strength can drive rapid overlapping ensemble formation. Thus, we propose a coordinated set of mechanisms by which acetylcholine release enables the selective encoding of salient high-density episodic memories in the hippocampus.

scholarly journals Separable actions of acetylcholine and noradrenaline on neuronal ensemble formation in hippocampal CA3 circuits

2021 ◽  
Vol 17 (10) ◽  
pp. e1009435
Author(s):  
Luke Y. Prince ◽  
Travis Bacon ◽  
Rachel Humphries ◽  
Krasimira Tsaneva-Atanasova ◽  
Claudia Clopath ◽  
...  
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Recurrent Network ◽  
Memory Storage ◽  
Neuronal Ensembles ◽  
Hippocampal Ca3 ◽  
Ca3 Pyramidal Cells ◽  
Episodic Memories ◽  
Mossy Fiber Pathway

In the hippocampus, episodic memories are thought to be encoded by the formation of ensembles of synaptically coupled CA3 pyramidal cells driven by sparse but powerful mossy fiber inputs from dentate gyrus granule cells. The neuromodulators acetylcholine and noradrenaline are separately proposed as saliency signals that dictate memory encoding but it is not known if they represent distinct signals with separate mechanisms. Here, we show experimentally that acetylcholine, and to a lesser extent noradrenaline, suppress feed-forward inhibition and enhance Excitatory–Inhibitory ratio in the mossy fiber pathway but CA3 recurrent network properties are only altered by acetylcholine. We explore the implications of these findings on CA3 ensemble formation using a hierarchy of models. In reconstructions of CA3 pyramidal cells, mossy fiber pathway disinhibition facilitates postsynaptic dendritic depolarization known to be required for synaptic plasticity at CA3-CA3 recurrent synapses. We further show in a spiking neural network model of CA3 how acetylcholine-specific network alterations can drive rapid overlapping ensemble formation. Thus, through these distinct sets of mechanisms, acetylcholine and noradrenaline facilitate the formation of neuronal ensembles in CA3 that encode salient episodic memories in the hippocampus but acetylcholine selectively enhances the density of memory storage.

Characteristics of local excitatory circuits studied with glutamate microapplication in the CA3 area of rat hippocampal slices

1988 ◽  
Vol 59 (1) ◽  
pp. 90-109 ◽  
Author(s):  
E. P. Christian ◽  
F. E. Dudek
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Firing Frequency ◽  
Block Transmission ◽  
Inhibitory Circuits ◽  
Axon Terminals ◽  
Stratum Pyramidale ◽  
Ca3 Pyramidal Cells

1. Local neuronal circuits in CA3 of hippocampal slices were studied by recording excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) intracellularly during glutamate microapplication in CA3. Control experiments validated this approach by providing evidence that glutamate microdrops stimulated neurons but not axons-of-passage or axon terminals in CA3. 2. Glutamate microdrops (10-20 mM, 10-20 microns diam) increased the firing frequency of extracellularly recorded dentate granule cells for 5–10 s when applied to their somata but not when applied to their mossy fiber axons and terminals in the hilus and in CA3. 3. Glutamate microapplications to granule cell somata, but not to mossy fiber axons, also increased the frequency of intracellularly recorded EPSPs in CA3 pyramidal cells for 5-10 s. This provided a second line of evidence that glutamate did not cause firing in mossy fiber axons synapsing in CA3. 4. In slices where the CA3 region was surgically separated from the dentate gyrus and CA2, glutamate microdrops placed in the CA3 stratum pyramidale within 400 microns of intracellularly recorded pyramidal cells increased the frequency of EPSPs and IPSPs. Tetrodotoxin (1 microgram/ml) blocked these increases in PSP frequency, indicating that they did not result from glutamate-induced depolarization and associated transmitter release from presynaptic terminals. Increases in PSP frequency were interpreted to reflect glutamate activations of CA3 neurons with local synaptic connections to recorded cells. 5. Low concentrations of picrotoxin (PTX, 5-10 microM) blocked glutamate-induced increases in IPSP frequency and often revealed increases in EPSP frequency where they were not previously observed. This suggests that recurrent inhibitory circuits normally mask or block transmission through recurrent excitatory pathways in CA3. 6. In five experiments following PTX treatment (7.5–10 microM), large and prolonged (up to 2 min) increases in EPSP frequency were observed in CA3 pyramidal cells to glutamate microapplications in CA3. Rhythmic epileptiform bursts eventually occurred in two of these cases, suggesting that the protracted increases in EPSP frequency represent a form of reverberating excitation during a transition from normal to epileptic states. 7. Sixteen CA3 pyramidal cells were recorded in PTX (5-10 microM) during glutamate microapplications at 200 and 400 microns on each side of the recording site. The most consistent glutamate-induced increases in EPSP frequency occurred to microapplications 200 microns from recording sites on the hilar side.(ABSTRACT TRUNCATED AT 400 WORDS)

Presynaptic Inhibition of Excitatory Afferents to Hilar Mossy Cells

2007 ◽  
Vol 97 (6) ◽  
pp. 4036-4047 ◽  
Author(s):  
Ben Nahir ◽  
Chinki Bhatia ◽  
Charles J. Frazier
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Muscarinic Acetylcholine Receptors ◽  
Memory Storage ◽  
Cholinergic Agonists ◽  
Mossy Cells ◽  
Excitatory Network ◽  
Ambient Gaba ◽  
Ca3 Pyramidal Cells

The hippocampus contains one very strong recurrent excitatory network formed by associational connections between CA3 pyramidal cells and another that depends largely on a disynaptic excitatory pathway between dentate granule cells. The recurrent excitatory network in CA3 has long been considered a possible location of autoassociative memory storage, whereas changes in the level and arrangement of recurrent excitation between granule cells are strongly implicated in epileptogenesis. Hilar mossy cells are likely to receive collateral input from CA3 pyramidal cells and they are key intermediaries (by mossy fiber inputs) in the recurrent excitatory network between granule cells. The current study uses minimal stimulation techniques in an in vitro preparation of the rat dentate gyrus to examine presynaptic modulation of both mossy fiber and non-mossy fiber inputs to hilar mossy cells. We report that both mossy fiber and non-mossy fiber inputs to hilar mossy cells express presynaptic γ-aminobutyric acid type B (GABAB) receptors that are subject to tonic inhibition by ambient GABA. We further find that only non-mossy fiber inputs express presynaptic muscarinic acetylcholine receptors, but that bath application of cholinergic agonists produces action potential–dependent increases in ambient GABA that can indirectly inhibit mossy fiber inputs. Finally, we demonstrate that mossy cells express high-affinity postsynaptic GABAA receptors that are also capable of detecting changes in ambient GABA produced by cholinergic agonists. Our results are among the first to directly characterize these important collateral inputs to hilar mossy cells and may help facilitate informed comparison between primary and collateral projections in two major excitatory pathways.

scholarly journals Plasticity-dependent, full detonation at hippocampal mossy fiber–CA3 pyramidal neuron synapses

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Nicholas P Vyleta ◽  
Carolina Borges-Merjane ◽  
Peter Jonas
Keyword(s):  
Granule Cells ◽  
Mossy Fiber ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Short Term ◽  
Short Term Plasticity ◽  
Cell Network ◽  
Post Tetanic Potentiation ◽  
Ca3 Pyramidal Cells ◽  
Ca3 Neurons

Mossy fiber synapses on CA3 pyramidal cells are 'conditional detonators' that reliably discharge postsynaptic targets. The 'conditional' nature implies that burst activity in dentate gyrus granule cells is required for detonation. Whether single unitary excitatory postsynaptic potentials (EPSPs) trigger spikes in CA3 neurons remains unknown. Mossy fiber synapses exhibit both pronounced short-term facilitation and uniquely large post-tetanic potentiation (PTP). We tested whether PTP could convert mossy fiber synapses from subdetonator into detonator mode, using a recently developed method to selectively and noninvasively stimulate individual presynaptic terminals in rat brain slices. Unitary EPSPs failed to initiate a spike in CA3 neurons under control conditions, but reliably discharged them after induction of presynaptic short-term plasticity. Remarkably, PTP switched mossy fiber synapses into full detonators for tens of seconds. Plasticity-dependent detonation may be critical for efficient coding, storage, and recall of information in the granule cell–CA3 cell network.

Evidence from simultaneous intracellular recordings in rat hippocampal slices that area CA3 pyramidal cells innervate dentate hilar mossy cells

1994 ◽  
Vol 72 (5) ◽  
pp. 2167-2180 ◽  
Author(s):  
H. E. Scharfman
Keyword(s):  
Pyramidal Cell ◽  
Action Potentials ◽  
Granule Cells ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Probability Of Failure ◽  
Mossy Cells ◽  
Mossy Cell ◽  
Ca3 Pyramidal Cells ◽  
Area Ca3

1. Simultaneous intracellular recordings of area CA3 pyramidal cells and dentate hilar “mossy” cells were made in rat hippocampal slices to test the hypothesis that area CA3 pyramidal cells excite mossy cells monosynaptically. Mossy cells and pyramidal cells were differentiated by location and electrophysiological characteristics. When cells were impaled near the border of area CA3 and the hilus, their identity was confirmed morphologically after injection of the marker Neurobiotin. 2. Evidence for monosynaptic excitation of a mossy cell by a pyramidal cell was obtained in 7 of 481 (1.4%) paired recordings. In these cases, a pyramidal cell action potential was followed immediately by a 0.40 to 6.75 (mean, 2.26) mV depolarization in the simultaneously recorded mossy cell (mossy cell membrane potentials, -60 to -70 mV). Given that pyramidal cells used an excitatory amino acid as a neurotransmitter (Cotman and Nadler 1987; Ottersen and Storm-Mathisen 1987) and recordings were made in the presence of the GABAA receptor antagonist bicuculline (25 microM), it is likely that the depolarizations were unitary excitatory postsynaptic potentials (EPSPs). 3. Unitary EPSPs of mossy cells were prone to apparent “failure.” The probability of failure was extremely high (up to 0.72; mean = 0.48) if the effects of all presynaptic action potentials were examined, including action potentials triggered inadvertently during other spontaneous EPSPs of the mossy cell. Probability of failure was relatively low (as low as 0; mean = 0.24) if action potentials that occurred during spontaneous activity of the mossy cell were excluded. These data suggest that unitary EPSPs produced by pyramidal cells are strongly affected by concurrent synaptic inputs to the mossy cell. 4. Unitary EPSPs were not clearly affected by manipulation of the mossy cell's membrane potential. This is consistent with the recent report that area CA3 pyramidal cells innervate distal dendrites of mossy cells (Kunkel et al. 1993). Such a distal location also may contribute to the high incidence of apparent failures. 5. Characteristics of unitary EPSPs generated by pyramidal cells were compared with the properties of the unitary EPSPs produced by granule cells. In two slices, pyramidal cell and granule cell inputs to the same mossy cell were compared. In other slices, inputs to different mossy cells were compared. In all experiments, unitary EPSPs produced by granule cells were larger in amplitude but similar in time course to unitary EPSPs produced by pyramidal cells. Probability of failure was lower and paired-pulse facilitation more common among EPSPs triggered by granule cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of tolbutamide on tetraethylammonium-induced postsynaptic zinc signals at hippocampal mossy fiber-CA3 synapses

2017 ◽  
Vol 95 (9) ◽  
pp. 1058-1063 ◽  
Author(s):  
Fatima C. Bastos ◽  
Vanessa N. Corceiro ◽  
Sandra A. Lopes ◽  
José G. de Almeida ◽  
Carlos M. Matias ◽  
...  
Keyword(s):  
Mossy Fiber ◽  
Mossy Fibers ◽  
Pyramidal Cells ◽  
Long Term Potentiation ◽  
Chemical Stimulation ◽  
Term Potentiation ◽  
Voltage Dependent ◽  
Zinc Release ◽  
Ca3 Pyramidal Cells

The application of tetraethylammonium (TEA), a blocker of voltage-dependent potassium channels, can induce long-term potentiation (LTP) in the synaptic systems CA3–CA1 and mossy fiber-CA3 pyramidal cells of the hippocampus. In the mossy fibers, the depolarization evoked by extracellular TEA induces a large amount of glutamate and also of zinc release. It is considered that zinc has a neuromodulatory role at the mossy fiber synapses, which can, at least in part, be due to the activation of presynaptic ATP-dependent potassium (KATP) channels. The aim of this work was to study properties of TEA-induced zinc signals, detected at the mossy fiber region, using the permeant form of the zinc indicator Newport Green. The application of TEA caused a depression of those signals that was partially blocked by the KATP channel inhibitor tolbutamide. After the removal of TEA, the signals usually increased to a level above baseline. These results are in agreement with the idea that intense zinc release during strong synaptic events triggers a negative feedback action. The zinc depression, caused by the LTP-evoking chemical stimulation, turns into potentiation after TEA washout, suggesting the existence of a correspondence between the observed zinc potentiation and TEA-evoked mossy fiber LTP.

scholarly journals Feedforward inhibition is randomly wired from individual granule cells onto CA3 pyramidal cells

Hippocampus ◽  
2017 ◽  
Vol 27 (10) ◽  
pp. 1034-1039 ◽  
Author(s):  
Máté Neubrandt ◽  
Viktor János Oláh ◽  
János Brunner ◽  
János Szabadics
Keyword(s):  
Granule Cells ◽  
Pyramidal Cells ◽  
Individual Granule ◽  
Ca3 Pyramidal Cells ◽  
Feedforward Inhibition

scholarly journals Are Altered Excitatory Synapses Found in Neuronal Migration Disorders?

2005 ◽  
Vol 5 (5) ◽  
pp. 171-173
Author(s):  
F. Edward Dudek
Keyword(s):  
Nmda Receptor ◽  
Knockout Mice ◽  
Neuronal Migration ◽  
Granule Cells ◽  
Seizure Activity ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Synaptic Response ◽  
Wild Type ◽  
Neuronal Migration Disorders

Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-out Mouse Hippocampus: Evidence for an Epileptic Circuit Patel LS, Wenzel HJ, Schwartzkroin PA J Neurosci 2004;24:9005–9014 There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether intrinsic features of the individual dysplastic cells give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knockout animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures. Extracellular field recordings from hippocampal slices, characterizing the input–output relation in the dentate, revealed little difference between wild-type and knockout mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABAA antagonist bicuculline, p35 knockout slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. No significant differences were found in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action-potential generation) from wild-type versus knockout mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in more than 65% of granule cells from p35 knockout slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knockout mice contribute to seizure activity by forming an abnormal excitatory feedback circuit. Prolonged NMDA-mediated Synaptic Response, Altered Ifenprodil Sensitivity, and Generation of Epileptiform-like Events in a Malformed Hippocampus of Rats Exposed to Methylazoxymethanol in Utero Calcagnotto ME, Baraban SC J Neurophysiol 2005 [Epub ahead of print] Cortical malformations are often associated with refractory epilepsy and cognitive deficit. Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions. With whole-cell voltage-clamp techniques, we examined evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation (i.e., rats exposed to methylazoxymethanol [MAM] in utero). Analysis of eEPSCs revealed that the late N-methyl-D-aspartate (NMDA) receptor–mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells. At a holding potential of +40 mV, heterotopic cells also exhibited eEPSCs with a slower decay-time constant. No differences in the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of eEPSCs were detected. In 23% of heterotopic pyramidal cells, electrical stimulation evoked prolonged burstlike responses. Focal application of glutamate (10 m M) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells. Ifenprodil (10 μM), an NR2B subunit antagonist, only slightly reduced the NMDA receptor–mediated component and amplitude of eEPSCs on heterotopic cells (MAM) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells (Control). Our data demonstrate a functional alteration in the NMDA-mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable, at least in part, to changes in composition and function of the NMDAR subunit. Changes in NMDA-receptor function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations.

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