scholarly journals Adaptive mossy cell circuit plasticity after status epilepticus

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.

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)

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

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.

K-dependent inhibition in the dentate-CA3 network of guinea pig hippocampal slices

1992 ◽  
Vol 68 (5) ◽  
pp. 1548-1557 ◽  
Author(s):  
U. Misgeld ◽  
M. Bijak ◽  
H. Brunner ◽  
K. Dembowsky
Keyword(s):  
Guinea Pig ◽  
Granule Cells ◽  
Hippocampal Slices ◽  
Granule Cell Layer ◽  
Postsynaptic Potentials ◽  
Burst Discharge ◽  
Mossy Cells ◽  
Discharge Activity ◽  
Dependent Inhibition ◽  
Hilar Neurons

1. The occurrence of potassium-dependent inhibitory postsynaptic potentials (K-IPSPs) in relation to burst discharges induced by 4-aminopyridine (4-AP; 30 microM) was studied in CA3, granule and hilar neurons in guinea pig hippocampal slices with the use of paired extra- and/or intracellular recording. 2. Slow small (2-5 mV) and large (up to 30 mV) K-IPSPs were observed in CA3, granule and in some hilar neurons during 4-AP applications in the presence of blockers for fast synaptic transmission, picrotoxin (50 microM), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 5-10 microM). Amplitudes of K-IPSPs were linearly related to voltage, and they reversed in sign close to -100 mV, as expected for synaptic potentials generated by an increase in K-conductance. 3. In CA3 neurons, 4-AP applied in the presence of picrotoxin elicited burst discharges and K-IPSPs. CNQX blocked the burst discharge activity and increased the amplitude of K-IPSPs. 4. In granule cells, 4-AP applied in the presence of picrotoxin elicited K-IPSPs and only inconsistently small excitatory postsynaptic potentials (EPSPs). The EPSPs were blocked by CNQX, but CNQX application did not affect the K-IPSPs. However, in granule cells it could be observed that blockade of Cl-inhibition by picrotoxin in the presence of CNQX increased the amplitude of K-IPSPs. 5. In hilar neurons, 4-AP applied in the presence of picrotoxin elicited mainly burst discharges. CNQX blocked the burst discharges only in a few cells. In most hilar neurons K-IPSPs were observed at the beginning of the 4-AP effect, but subsequently K-IPSPs were replaced by burst discharges. 6. To determine the type of cells that burst in picrotoxin and 4-AP, neurons were stained intracellularly with horseradish peroxidase. Neurons stained in the granule cell layer did not burst and were morphologically identified as granule cells. Neurons stained in the hilar region burst and were nonpyramidal, nongranule cells. Bursting cells stained in the CA3 area were all pyramidal cells. 7. The hilar neurons varied considerably in size and dendritic organization. They could be classified as aspiny and spiny cells, the latter including mossy cells. 8. We conclude that K-dependent inhibition may explain the long-lasting IPSPs observed in in vivo recordings from hippocampal cells. In a hippocampal lamella, burst discharge activity of hilar neurons including presumed excitatory mossy cells is associated with inhibition of granule cells.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Enhanced Tonic GABA Current in Normotopic and Hilar Ectopic Dentate Granule Cells After Pilocarpine-Induced Status Epilepticus

2009 ◽  
Vol 102 (2) ◽  
pp. 670-681 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
J. Victor Nadler
Keyword(s):  
Plasma Membrane ◽  
Status Epilepticus ◽  
Action Potential ◽  
Dentate Gyrus ◽  
Membrane Transport ◽  
Granule Cells ◽  
Hippocampal Slices ◽  
Gaba Concentration ◽  
Dentate Granule Cells ◽  
Gaba Inhibition

In temporal lobe epilepsy, loss of inhibitory neurons and circuit changes in the dentate gyrus promote hyperexcitability. This hyperexcitability is compensated to the point that dentate granule cells exhibit normal or even subnormal excitability under some conditions. This study explored the possibility that compensation involves enhanced tonic GABA inhibition. Whole cell patch-clamp recordings were made from normotopic granule cells in hippocampal slices from control rats and from both normotopic and hilar ectopic granule cells in slices from rats subjected to pilocarpine-induced status epilepticus. After status epilepticus, tonic GABA current was an order of magnitude greater than control in normotopic granule cells and was significantly greater in hilar ectopic than in normotopic granule cells. These differences could be observed whether or not the extracellular GABA concentration was increased by adding GABA to the superfusion medium or blocking plasma membrane transport. The enhanced tonic GABA current had both action potential–dependent and action potential–independent components. Pharmacological studies suggested that the small tonic GABA current of granule cells in control rats was mediated largely by high-affinity α4βxδ GABAA receptors but that the much larger current recorded after status epilepticus was mediated largely by the lower-affinity α5βxγ2 GABAA receptors. A large α5βxγ2-mediated tonic current could be recorded from controls only when the extracellular GABA concentration was increased. Status epilepticus seemed not to impair the control of extracellular GABA concentration by plasma membrane transport substantially. Upregulated tonic GABA inhibition may account for the unexpectedly modest excitability of the dentate gyrus in epileptic brain.

scholarly journals Selective Changes in Hippocampal GABAA Receptors during Status Epilepticus

2008 ◽  
Vol 8 (6) ◽  
pp. 170-172
Author(s):  
Gregory C. Mathews
Keyword(s):  
Status Epilepticus ◽  
Ligand Binding ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
External Medium ◽  
Hippocampal Slices ◽  
Surface Expression ◽  
Hippocampal Pyramidal Neurons ◽  
Electrophysiological Recordings ◽  
Reduced Surface

Subunit-Specific Trafficking of >GABAA Receptors During Status Epilepticus. Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J. J Neurosci 2008 5;28(10):2527–2538. It is proposed that a reduced surface expression of GABAA receptors (GABARs) contributes to the pathogenesis of status epilepticus (SE), a condition characterized by prolonged seizures. This hypothesis was based on the finding that prolonged epileptiform bursting (repetitive bursts of prolonged depolarizations with superimposed action potentials) in cultures of dissociated hippocampal pyramidal neurons (dissociated cultures) results in the increased intracellular accumulation of GABARs. However, it is not known whether this rapid modification in the surface-expressed GABAR pool results from selective, subunit-dependent or nonselective, subunit-independent internalization of GABARs. In hippocampal slices obtained from animals undergoing prolonged SE (SE-treated slices), we found that the surface expression of the GABAR β2/3 and γ2 subunits was reduced, whereas that of the δ subunit was not. Complementary electrophysiological recordings from dentate granule cells in SE-treated slices demonstrated a reduction in GABAR-mediated synaptic inhibition, but not tonic inhibition. A reduction in the surface expression of the γ2 subunit, but not the δ subunit was also observed in dissociated cultures and organotypic hippocampal slice cultures when incubated in an elevated KCl external medium or an elevated KCl external medium supplemented with NMDA, respectively. Additional studies demonstrated that the reduction in the surface expression of the γ2 subunit was independent of direct ligand binding of the GABAR. These findings demonstrate that the regulation of surface-expressed GABAR pool during SE is subunit-specific and occurs independent of ligand binding. The differential modulation of the surface expression of GABARs during SE has potential implications for the treatment of this neurological emergency.

Role of Mossy Fiber Sprouting and Mossy Cell Loss in Hyperexcitability: A Network Model of the Dentate Gyrus Incorporating Cell Types and Axonal Topography

2005 ◽  
Vol 93 (1) ◽  
pp. 437-453 ◽  
Author(s):  
Vijayalakshmi Santhakumar ◽  
Ildiko Aradi ◽  
Ivan Soltesz
Keyword(s):  
Dentate Gyrus ◽  
Mossy Fiber ◽  
Cell Loss ◽  
Perforant Path ◽  
In Vivo Studies ◽  
Recent Experimental Data ◽  
Mossy Fiber Sprouting ◽  
Mossy Cells ◽  
Mossy Cell

Mossy cell loss and mossy fiber sprouting are two characteristic consequences of repeated seizures and head trauma. However, their precise contributions to the hyperexcitable state are not well understood. Because it is difficult, and frequently impossible, to independently examine using experimental techniques whether it is the loss of mossy cells or the sprouting of mossy fibers that leads to dentate hyperexcitability, we built a biophysically realistic and anatomically representative computational model of the dentate gyrus to examine this question. The 527-cell model, containing granule, mossy, basket, and hilar cells with axonal projections to the perforant-path termination zone, showed that even weak mossy fiber sprouting (10–15% of the strong sprouting observed in the pilocarpine model of epilepsy) resulted in the spread of seizure-like activity to the adjacent model hippocampal laminae after focal stimulation of the perforant path. The simulations also indicated that the spatially restricted, lamellar distribution of the sprouted mossy fiber contacts reported in in vivo studies was an important factor in sustaining seizure-like activity in the network. In contrast to the robust hyperexcitability-inducing effects of mossy fiber sprouting, removal of mossy cells resulted in decreased granule cell responses to perforant-path activation in agreement with recent experimental data. These results indicate the crucial role of mossy fiber sprouting even in situations where there is only relatively weak mossy fiber sprouting as is the case after moderate concussive experimental head injury.

Roles of Very Fast Ripple (500–1000Hz) in the Hippocampal Network During Status Epilepticus

2020 ◽  
pp. 2150002
Author(s):  
Jianmin Hao ◽  
Yan Cui ◽  
Bochao Niu ◽  
Liang Yu ◽  
Yuhang Lin ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Temporal Lobe ◽  
Phase Locking ◽  
Epileptic Seizures ◽  
Network Activity ◽  
Slow Oscillations ◽  
Functional Roles ◽  
High Frequency Oscillations ◽  
Epileptiform Discharges ◽  
Hippocampal Network

Very fast ripples (VFRs, 500–1000[Formula: see text]Hz) are considered more specific than high-frequency oscillations (80–500[Formula: see text]Hz) as biomarkers of epileptogenic zones. Although VFRs are frequent abnormal phenomena in epileptic seizures, their functional roles remain unclear. Here, we detected the VFRs in the hippocampal network and tracked their roles during status epilepticus (SE) in rats with pilocarpine-induced temporal lobe epilepsy (TLE). All regions in the hippocampal network exhibited VFRs in the baseline, preictal, ictal and postictal states, with the ictal state containing the most VFRs. Moreover, strong phase-locking couplings existed between VFRs and slow oscillations (1–12[Formula: see text]Hz) in the ictal and postictal states for all regions. Further investigation indicated that during VFRs, the build-up of slow oscillations in the ictal state began from the temporal lobe and then spread through the whole hippocampal network via two different pathways, which might be associated with the underlying propagation of epileptiform discharges in the hippocampal network. Overall, we provide a functional description of the emergence of VFRs in the hippocampal network during SE, and we also establish that VFRs may be the physiological representation of the pathological alterations in hippocampal network activity during SE in TLE.

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

1995 ◽  
Vol 74 (1) ◽  
pp. 179-194 ◽  
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.

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

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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