Localization of Brain-Derived Neurotrophic Factor to Distinct Terminals of Mossy Fiber Axons Implies Regulation of Both Excitation and Feedforward Inhibition of CA3 Pyramidal Cells

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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Actions of Brain-Derived Neurotrophic Factor in Slices from Rats with Spontaneous Seizures and Mossy Fiber Sprouting in the Dentate Gyrus

Journal of Neuroscience ◽

10.1523/jneurosci.19-13-05619.1999 ◽

1999 ◽

Vol 19 (13) ◽

pp. 5619-5631 ◽

Cited By ~ 85

Author(s):

Helen E. Scharfman ◽

Jeffrey H. Goodman ◽

Anne L. Sollas

Keyword(s):

Dentate Gyrus ◽

Neurotrophic Factor ◽

Mossy Fiber ◽

Brain Derived Neurotrophic Factor ◽

Mossy Fiber Sprouting ◽

Spontaneous Seizures

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

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0379 ◽

2017 ◽

Vol 95 (9) ◽

pp. 1058-1063 ◽

Cited By ~ 1

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.

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

Hippocampus ◽

10.1002/hipo.22763 ◽

2017 ◽

Vol 27 (10) ◽

pp. 1034-1039 ◽

Cited By ~ 4

Author(s):

Máté Neubrandt ◽

Viktor János Oláh ◽

János Brunner ◽

János Szabadics

Keyword(s):

Granule Cells ◽

Pyramidal Cells ◽

Individual Granule ◽

Ca3 Pyramidal Cells ◽

Feedforward Inhibition

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Recruitment of an inhibitory hippocampal network after bursting in a single granule cell

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0702164104 ◽

2007 ◽

Vol 104 (18) ◽

pp. 7640-7645 ◽

Cited By ~ 27

Author(s):

Masahiro Mori ◽

Beat H. Gähwiler ◽

Urs Gerber

Keyword(s):

Pyramidal Cell ◽

Granule Cell ◽

Mossy Fiber ◽

Mossy Fibers ◽

Pyramidal Cells ◽

Network Activity ◽

Inhibitory Input ◽

Inhibitory Interneurons ◽

Failure Rates ◽

Ca3 Pyramidal Cells

The hippocampal CA3 area, an associational network implicated in memory function, receives monosynaptic excitatory as well as disynaptic inhibitory input through the mossy-fiber axons of the dentate granule cells. Synapses made by mossy fibers exhibit low release probability, resulting in high failure rates at resting discharge frequencies of 0.1 Hz. In recordings from functionally connected pairs of neurons, burst firing of a granule cell increased the probability of glutamate release onto both CA3 pyramidal cells and inhibitory interneurons, such that subsequent low-frequency stimulation evoked biphasic excitatory/inhibitory responses in a CA3 pyramidal cell, an effect lasting for minutes. Analysis of the unitary connections in the circuit revealed that granule cell bursting caused powerful activation of an inhibitory network, thereby transiently suppressing excitatory input to CA3 pyramidal cells. This phenomenon reflects the high incidence of spike-to-spike transmission at granule cell to interneuron synapses, the numerically much greater targeting by mossy fibers of inhibitory interneurons versus principal cells, and the extensively divergent output of interneurons targeting CA3 pyramidal cells. Thus, mossy-fiber input to CA3 pyramidal cells appears to function in three distinct modes: a resting mode, in which synaptic transmission is ineffectual because of high failure rates; a bursting mode, in which excitation predominates; and a postbursting mode, in which inhibitory input to the CA3 pyramidal cells is greatly enhanced. A mechanism allowing the transient recruitment of inhibitory input may be important for controlling network activity in the highly interconnected CA3 pyramidal cell region.

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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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Hyperexcitability in Combined Entorhinal/Hippocampal Slices of Adult Rat After Exposure to Brain-Derived Neurotrophic Factor

Journal of Neurophysiology ◽

10.1152/jn.1997.78.2.1082 ◽

1997 ◽

Vol 78 (2) ◽

pp. 1082-1095 ◽

Cited By ~ 111

Author(s):

Helen E. Scharfman

Keyword(s):

Entorhinal Cortex ◽

Neurotrophic Factor ◽

Mossy Fiber ◽

Hippocampal Slices ◽

Brain Derived Neurotrophic Factor ◽

Field Potentials ◽

Adult Rat ◽

Bath Application ◽

Fiber Stimulation ◽

Area Ca3

Scharfman, Helen E. Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J. Neurophysiol. 78: 1082–1095, 1997. Effects of brain-derived neurotrophic factor (BDNF) in area CA3, the dentate gyrus, and medial entorhinal cortex were examined electrophysiologically by bath application of BDNF in slices containing the hippocampus and entorhinal cortex. Bath application of 25–100 ng/ml BDNF for 30–90 min increased responses to single afferent stimuli in selective pathways in the majority of slices. In area CA3, responses to mossy fiber stimulation increased in 73% of slices and entorhinal cortex responses to white matter stimulation increased in 64% of slices. After exposure to BDNF, these areas also demonstrated evidence of hyperexcitability, because responses to repetitive stimulation (1-Hz paired pulses for several s) produced multiple population spikes in response to mossy fiber stimulation in CA3 or multiple field potentials in response to white matter stimulation in the entorhinal cortex. Repetitive field potentials persisted after repetitive stimulation ended and usually were followed by spreading depression. Enhancement of responses to single stimuli and hyperexcitability were never evoked in untreated slices or after bath application of boiled BDNF or cytochrome C. The tyrosine kinase antagonist K252a (2 μM) blocked the effects of BDNF. In area CA3, both the potentiation of responses to single stimuli and hyperexcitability showed afferent specificity, because responses to mossy fiber stimulation were affected but responses to fimbria or Schaffer collateral stimulation were not. In addition, regional specificity was demonstrated in that the dentate gyrus was much less affected. The effects of BDNF in area CA3 were similar to those produced by bath application of low doses of kainic acid, which is thought to modulate glutamate release from mossy fiber terminals by a presynaptic action. These results suggest that BDNF has acute effects on excitability in different areas of the hippocampal-entorhinal circuit. These effects appear to be greatest in areas that are highly immunoreactive for BDNF, such as the mossy fibers and the entorhinal cortex. Although the present experiments do not elucidate mechanism(s) definitively, the afferent specificity, similarity to the effects of kainic acid, and block by K252a are consistent with previous hypotheses that BDNF affects acute excitability by a presynaptic action on trkB receptors that modulate excitatory amino acid transmission. However, we cannot rule out actions on inhibitory synapses or postsynaptic processes.

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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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Kainate Receptor–Mediated Inhibition of Glutamate Release Involves Protein Kinase A in the Mouse Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00280.2006 ◽

2006 ◽

Vol 96 (4) ◽

pp. 1829-1837 ◽

Cited By ~ 33

Author(s):

José V. Negrete-Díaz ◽

Talvinder S. Sihra ◽

José M. Delgado-García ◽

Antonio Rodríguez-Moreno

Keyword(s):

Protein Kinase ◽

Protein Kinase A ◽

Mossy Fiber ◽

Glutamate Release ◽

Pyramidal Cells ◽

Kainate Receptors ◽

Mouse Hippocampus ◽

Ca3 Pyramidal Cells ◽

Kinase A ◽

Stimulation Of

The mechanisms involved in the inhibition of glutamate release mediated by the activation of presynaptic kainate receptors (KARs) at the hippocampal mossy fiber–CA3 synapse are not well understood. We have observed a long-lasting inhibition of CA3 evoked excitatory postsynaptic currents (eEPSCs) after a brief application of kainate (KA) at concentrations ranging from 0.3 to 10 μM. The inhibition outlasted the change in holding current caused by the activation of ionotropic KARs in CA3 pyramidal cells, indicating that this action is not contingent on the opening of the receptor channels. The inhibition of the eEPSCs by KA was prevented by G protein and protein kinase A (PKA) inhibitors and was enhanced after stimulation of the adenylyl cyclase (AC) with forskolin. We conclude that KARs present at mossy fiber terminals mediate the inhibition of glutamate release through a metabotropic mechanism that involves the activation of an AC-second messenger cAMP-PKA signaling cascade.

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