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

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.

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

10.1101/201699 ◽

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.

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Presynaptic Inhibition of Excitatory Afferents to Hilar Mossy Cells

Journal of Neurophysiology ◽

10.1152/jn.00069.2007 ◽

2007 ◽

Vol 97 (6) ◽

pp. 4036-4047 ◽

Cited By ~ 11

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.

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

Journal of Neurophysiology ◽

10.1152/jn.1988.59.1.90 ◽

1988 ◽

Vol 59 (1) ◽

pp. 90-109 ◽

Cited By ~ 64

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)

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Selective death of hippocampal CA3 pyramidal cells with mossy fiber afferents after CRH-induced status epilepticus in infant rats

Developmental Brain Research ◽

10.1016/0165-3806(95)00183-2 ◽

1996 ◽

Vol 91 (2) ◽

pp. 245-251 ◽

Cited By ~ 48

Author(s):

Charles E. Ribak ◽

Tallie Z. Baram

Keyword(s):

Status Epilepticus ◽

Mossy Fiber ◽

Pyramidal Cells ◽

Infant Rats ◽

Hippocampal Ca3 ◽

Ca3 Pyramidal Cells ◽

Selective Death

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GABAA-Dependent Chloride Influx Modulates GABAB-Mediated IPSPs in Hippocampal Pyramidal Cells

Journal of Neurophysiology ◽

10.1152/jn.1999.82.3.1218 ◽

1999 ◽

Vol 82 (3) ◽

pp. 1218-1223 ◽

Cited By ~ 12

Author(s):

Valeri Lopantsev ◽

Philip A. Schwartzkroin

Keyword(s):

Membrane Potential ◽

Mossy Fiber ◽

Pyramidal Cells ◽

Potassium Acetate ◽

Membrane Potentials ◽

Resting Membrane Potential ◽

Receptor Antagonists ◽

Hippocampal Ca3 ◽

Ca3 Pyramidal Cells ◽

Chloride Influx

The relationship between postsynaptic inhibitory responses [the fast GABAA-mediated inhibitory postsynaptic potential (IPSP) and the slow GABAB-mediated IPSP] were investigated in hippocampal CA3 pyramidal cells. Mossy fiber-evoked GABAB-mediated IPSPs were, paradoxically, of greater amplitude in cells with resting membrane potential of −62 mV (13.6 ± 0.5 mV; mean ± SE) as compared with cells with resting membrane potential of −54 mV (7.0 ± 0.8 mV). In addition, when a cell’s membrane potential was artificially manipulated, GABAB-mediated IPSPs were reduced at relatively depolarized levels (−55 mV) and enhanced at relatively hyperpolarized potentials (at least −60 mV). In contrast, the preceding GABAA-mediated IPSPs were larger at the more positive membrane potentials and smaller as the cell was hyperpolarized. Similar voltage dependency was obtained when monosynaptic GABAA- and GABAB-mediated IPSPs were isolated in the presence of glutamatergic receptor antagonists. However, monosynaptic GABAB-mediated IPSPs isolated in the presence of glutamatergic and GABAA receptor antagonists were not reduced at the more positive membrane potentials, and were significantly larger in amplitude than GABAB-mediated IPSPs preceded by a monosynaptic GABAA-mediated IPSP. The amplitude of the isolated monosynaptic GABAB-mediated IPSPs recorded with potassium chloride-containing microelectrodes was significantly smaller than the comparable potential recorded with potassium acetate microelectrodes without chloride. We conclude that voltage-dependent chloride influx, via GABAA receptor-gated channels, modulates postsynaptic GABAB-mediated inhibition in hippocampal CA3 pyramidal cells.

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Intracellular Zn2+ Signaling Facilitates Mossy Fiber Input-Induced Heterosynaptic Potentiation of Direct Cortical Inputs in Hippocampal CA3 Pyramidal Cells

Journal of Neuroscience ◽

10.1523/jneurosci.2130-18.2019 ◽

2019 ◽

Vol 39 (20) ◽

pp. 3812-3831 ◽

Cited By ~ 3

Author(s):

Kisang Eom ◽

Jung Ho Hyun ◽

Dong-gu Lee ◽

Sooyun Kim ◽

Hyeon-Ju Jeong ◽

...

Keyword(s):

Mossy Fiber ◽

Pyramidal Cells ◽

Hippocampal Ca3 ◽

Heterosynaptic Potentiation ◽

Ca3 Pyramidal Cells ◽

Cortical Inputs

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

eLife ◽

10.7554/elife.17977 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 34

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.

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