Single synapses control mossy cell firing

AbstractThe function of mossy cells (MCs) in the dentate gyrus has remained elusive. Here we determined the functional impact of single mossy fibre (MF) synapses on MC firing in mouse entorhino-hippocampal slice cultures. We stimulated single MF boutons and recorded Ca2+ transients in the postsynaptic spine and unitary excitatory postsynaptic potentials (EPSPs) at the MC soma. Synaptic responses to single presynaptic stimuli varied strongly between different MF synapses, even if they were located on the same MC dendrite. Synaptic strengths ranged from subthreshold EPSPs to direct postsynaptic action potential (AP) generation. Induction of synaptic plasticity at these individual MF synapses resulted in potentiation or depression depending on the initially encountered synaptic state, indicating that synaptic transmission at MF synapses on MCs is determined by their previous functional history. With these unique functional properties MF-MC synapses control MC firing individually thereby enabling modulation of the dentate network by single granule cells.

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

Journal of Neurophysiology ◽

10.1152/jn.1994.72.5.2167 ◽

1994 ◽

Vol 72 (5) ◽

pp. 2167-2180 ◽

Cited By ~ 83

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)

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Focal synaptic potentials due to discrete mossy-fibre arrival volleys in the cerebellar cortex

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1987.0042 ◽

1987 ◽

Vol 231 (1263) ◽

pp. 217-230 ◽

Cited By ~ 3

Keyword(s):

Cerebellar Cortex ◽

Granule Cells ◽

Molecular Layer ◽

Field Potential ◽

Mossy Fibre ◽

Synaptic Potential ◽

Presynaptic Spike ◽

Cell Firing ◽

Mossy Fibres ◽

Afferent Volleys

The previously described direct and relayed projections of periodontal afferents to the cerebellar cortex have been examined in detail by extracellular field-potential analysis. Advantage is taken of the very small temporal dispersion of the afferent volleys to permit identification of the presynaptic spike potential of mossy fibres, the subsequent synaptic potential and the firing of granule cells. Changes in form of the presynaptic potential with depth are compared with published descriptions of presynaptic potentials elsewhere. The negative synaptic potential in the granular layer is shown to have a positive aspect in the molecular layer. Granule-cell firing can, under some conditions, yield a population spike interrupting the synaptic potential wave. Records are presented showing all-or-none complex waves, which appear to be single glomerular potentials not previously described in the mammalian cerebellum. Their distinction from cellular spike potentials is emphasized.

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Electrophysiological evidence that dentate hilar mossy cells are excitatory and innervate both granule cells and interneurons

Journal of Neurophysiology ◽

10.1152/jn.1995.74.1.179 ◽

1995 ◽

Vol 74 (1) ◽

pp. 179-194 ◽

Cited By ~ 115

Author(s):

H. E. Scharfman

Keyword(s):

Membrane Potential ◽

Action Potential ◽

Gabaa Receptor ◽

Granule Cell ◽

Granule Cells ◽

Resting Potential ◽

Mossy Cells ◽

Mossy Cell ◽

The Mean ◽

Monosynaptic Excitation

1. The hypothesis that dentate hilar "mossy" cells are excitatory was tested by simultaneous intracellular recording in rat hippocampal slices. Mossy cells were recorded simultaneously with their potential targets, granule cells and interneurons. The gamma-amino-butyric acid-A (GABAA) receptor antagonist bicuculline was used in most experiments to block the normally strong inhibitory inputs to granule cells that could mask excitatory effects of mossy cells. Some cells were recorded with electrodes containing the marker Neurobiotin so that their identity could be confirmed morphologically. 2. A mossy cell action potential was immediately followed by a brief depolarization in a granule cell in 20 of 1,316 pairs (1.5%) that were recorded in the presence of bicuculline. The mean amplitude of depolarizations was 1.99 +/- 0.24 (SE) mV when the postsynaptic membrane potential was -55 to -65 mV. Depolarizations could trigger an action potential if the granule cell was depolarized from its resting potential so that its membrane potential was -50 to -60 mV. These data suggest that mossy cells excite granule cells monosynaptically. 3. Monosynaptic excitation of an interneuron by a mossy cell was recorded in 4 of 47 (8.5%) simultaneously recorded mossy cells and interneurons, also in the presence of bicuculline. The mean interneuron depolarization was 1.64 +/- 0.29 mV when the interneuron membrane potential was approximately -60 mV. When an interneuron was at its resting potential (-52 to -63 mV), action potentials were often triggered by the depolarizations. 4. Without bicuculline present, mossy cells had no apparent monosynaptic effects on granule cells, as has been previously reported. However, effects that appeared to be polysynaptic were observed in 5 of 92 pairs (5.4%). Specifically, a small, brief hyperpolarization occurred in granule cells 2.5-7.3 ms after the peak of a mossy cell action potential. Given the results indicating that mossy cells excite interneurons, and the long latency to onset of the hyperpolarization, one possible explanation for the hyperpolarization is that mossy cells excited interneurons that inhibited granule cells. 5. The results suggest that mossy cells are excitatory neurons. In addition, mossy cells appear to innervate both granule cells and interneurons that are located within several hundred micrometers of the mossy cell soma. The only detectable effect on granule cells in this area under normal conditions appears to be disynaptic and inhibitory. However, when GABAA-receptor-mediated inhibition is blocked, monosynaptic excitation of granule cells by mossy cells can be detected.

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Excitatory effects of dentate gyrus mossy cells and their ability to influence granule cell firing: an optogenetic study in adult mouse hippocampal slices

10.1101/2020.06.06.137844 ◽

2020 ◽

Author(s):

Hannah L. Bernstein ◽

Yi-Ling Lu ◽

Justin J. Botterill ◽

Áine M. Duffy ◽

John J. LaFrancois ◽

...

Keyword(s):

Dentate Gyrus ◽

Granule Cells ◽

Molecular Layer ◽

Hippocampal Slices ◽

Gabaergic Neurons ◽

Excitatory Effect ◽

Experimental Conditions ◽

Mossy Cells ◽

Direct Excitation ◽

Cell Firing

ABSTRACTGlutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary cell type, granule cells (GCs), and GABAergic neurons which inhibit GCs. Prior studies suggest that the net effect of MCs is mainly to inhibit GCs, leading one to question why direct excitation of GCs is often missed. We hypothesized that MCs do have excitatory effects, but each GC is only excited weakly, at least under most experimental conditions. To address this hypothesis, MC axons were stimulated optogenetically in slices. A brief optogenetic stimulus to MC axons in the inner molecular layer (IML) led to a short-latency field EPSP (fEPSP) in the IML, suggesting there was a direct excitatory effect on GCs. Population spikes were negligible however, consistent with weak excitation. FEPSPs reflected AMPA/NMDA receptor-mediated EPSPs in GCs. EPSPs reached threshold after GC depolarization or facilitating NMDA receptors. GABAA and GABAB receptor-mediated IPSPs often followed EPSPs. At the network level, an optogenetic stimulus led to a brief, small facilitation of the PP-evoked population spike followed by a longer, greater inhibition. These data are consistent with rapid and selective GC firing by MCs (MC → GC) and disynaptic inhibition (MC → GABAergic neuron → GC). Notably, optogenetic excitation was evoked for both dorsal and ventral MCs, ipsilateral and contralateral MC axons, and two Cre lines. Together the results suggest a way to reconcile past studies and provide new insight into the balance of excitation and inhibition of GCs by MCs.SIGNIFICANCE STATEMENTMossy cells (MCs) of the dentate gyrus (DG) are glutamatergic and innervate granule cells (GCs). The net effect of MCs has been debated because MCs also innervate GABAergic neurons which inhibit GCs. The results shown here suggest that MCs excite numerous GCs, but excitation is weak at GC resting potentials, and requires specific conditions to trigger GC APs. The results are consistent with a GC network that is designed for selective activation.

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Adaptive mossy cell circuit plasticity after status epilepticus

10.1101/2021.04.12.439511 ◽

2021 ◽

Author(s):

Corwin R. Butler ◽

Gary L. Westbrook ◽

Eric Schnell

Keyword(s):

Status Epilepticus ◽

Granule Cells ◽

Hippocampal Slices ◽

Epileptic Seizures ◽

Cell Loss ◽

Inhibitory Effect ◽

Network Activity ◽

Mossy Cells ◽

Direct Excitation ◽

Mossy Cell

SummaryHilar mossy cells control network function in the hippocampus through both direct excitation and di-synaptic inhibition of dentate granule cells (DGCs). Substantial mossy cell loss occurs after epileptic seizures; however the contribution of surviving mossy cells to network activity in the reorganized dentate gyrus is unknown. To examine functional circuit changes after pilocarpine-induced status epilepticus, we optogenetically stimulated mossy cells in acute hippocampal slices. In control mice, activation of mossy cells produced monosynaptic excitatory and di-synaptic GABAergic currents in DGCs. In pilocarpine-treated mice, mossy cell density and excitation of DGCs were reduced in parallel, with only a minimal reduction in feedforward inhibition, enhancing the inhibition:excitation ratio. Surprisingly, mossy cell-driven excitation of parvalbumin-positive basket cells, the primary mediators of feed-forward inhibition, was maintained, indicating increased connectivity between surviving mossy cells and these targets. Our results suggest that mossy cell outputs reorganize following seizures, increasing their net inhibitory effect in the hippocampus.

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Dopamine Modulates Homeostatic Excitatory Synaptic Plasticity of Immature Dentate Granule Cells in Entorhino-Hippocampal Slice Cultures

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2018.00303 ◽

2018 ◽

Vol 11 ◽

Cited By ~ 3

Author(s):

Andreas Strehl ◽

Christos Galanis ◽

Tijana Radic ◽

Stephan Wolfgang Schwarzacher ◽

Thomas Deller ◽

...

Keyword(s):

Synaptic Plasticity ◽

Hippocampal Slice ◽

Granule Cells ◽

Dentate Granule Cells ◽

Hippocampal Slice Cultures

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Ventral hippocampal mossy cell hyperactivity degrades dorsal hippocampal mnemonic function via longitudinal projections

10.1101/2020.12.15.422938 ◽

2020 ◽

Author(s):

James P Bauer ◽

Sarah L Rader ◽

Max Joffe ◽

Wooseok Kwon ◽

Juliana Quay ◽

...

Keyword(s):

Dentate Gyrus ◽

Granule Cells ◽

Memory Task ◽

Longitudinal Axis ◽

Motor Behaviors ◽

Mossy Cells ◽

Object Location Memory ◽

Dorsal Hippocampal ◽

Mossy Cell

The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive compared to healthy controls. In rodent models of schizophrenia etiology, the ventral hippocampus, analogous to the human anterior hippocampus, is also hyperactive with effects on extrahippocampal neural circuits that might contribute to positive, negative, and cognitive symptoms. Less is known about how anterior hippocampal hyperactivity might directly influence intrahippocampal function across the structure's longitudinal axis. This question is important for understanding cognitive dysfunction in schizophrenia, which includes deficits attributed to both the anterior and posterior hippocampus. We hypothesized that hyperactivity of ventral hippocampal mossy cells, which send dense longitudinal projections throughout the hippocampal longitudinal axis, may be sufficient to disrupt spatial memory encoding, a dorsal hippocampal-dependent function. Using an intersectional viral strategy, we targeted ventral mossy cells projecting to the dorsal dentate gyrus. In vivo fiber photometry revealed these cells were activated during behavior related to context mapping but not during non-exploratory motor behaviors. Anterograde transsynaptic tracing and optogenetic terminal stimulation revealed functional connectivity between ventral mossy cells and dorsal dentate gyrus granule cells. Finally, chemogenetic activation of ventral mossy cells during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors. These findings suggest that anterior hippocampal hyperactivity may have intrahippocampal consequences to degrade posterior hippocampal function and support future studies engaging this circuit target to mitigate specific cognitive deficits associated with schizophrenia.

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