Epileptogenesis Is Associated With Enhanced Glutamatergic Transmission in the Perforant Path

2006 ◽  
Vol 95 (2) ◽  
pp. 1213-1220 ◽  
Author(s):  
Annalisa Scimemi ◽  
Stephanie Schorge ◽  
Dimitri M. Kullmann ◽  
Matthew C. Walker
Keyword(s):  
Status Epilepticus ◽  
Nmda Receptor ◽  
Temporal Lobe ◽  
Cross Talk ◽  
Granule Cells ◽  
Perforant Path ◽  
Seizure Threshold ◽  
Glutamatergic Transmission ◽  
Dentate Granule Cells ◽  
Receptor Kinetics

The perforant path provides the main excitatory input into the hippocampus and has been proposed to play a critical role in the generation of temporal lobe seizures. It has been hypothesized that changes in glutamatergic transmission in this pathway promote the epileptogenic process and seizure generation. We therefore asked whether epileptogenesis is associated with enhanced glutamatergic transmission from the perforant path to dentate granule cells. We used a rat model of temporal lobe epilepsy in which spontaneous seizures occur after an episode of pilocarpine-induced status epilepticus. Whole cell patch-clamp recordings were obtained from dentate granule cells in hippocampal slices from control and epileptic animals 3 wk after pilocarpine-induced status epilepticus. The paired pulse ratio of perforant path-evoked AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) was reduced in tissue obtained from epileptic rats. This is consistent with an increase in release probability. N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs were also prolonged. This prolongation could not be accounted for by decreased activity of glutamate transporters or by a change in NMDA receptor subunit composition in dentate granule cells, implying a change in NMDA receptor kinetics. This change in NMDA receptor kinetics was associated with the emergence of significant synaptic cross-talk, detected as a use-dependent block of receptors activated by medial perforant path synapses after lateral perforant path stimulation in MK-801. Enhanced glutamatergic transmission and the emergence of cross-talk among perforant path-dentate granule cell synapses may contribute to lowering seizure threshold.

Glutamate Currents in Morphologically Identified Human Dentate Granule Cells in Temporal Lobe Epilepsy

1997 ◽  
Vol 77 (6) ◽  
pp. 3355-3369 ◽  
Author(s):  
Masako Isokawa ◽  
Michel Levesque ◽  
Itzhak Fried ◽  
Jerome Engel
Keyword(s):  
Nmda Receptor ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Spine Density ◽  
Postsynaptic Potentials ◽  
Dentate Granule Cells ◽  
Current Voltage ◽  
Current Voltage Relationship ◽  
Voltage Relationship

Isokawa, Masako, Michel Levesque, Itzhak Fried, and Jerome Engel, Jr. Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy. J. Neurophysiol. 77: 3355–3369, 1997. Glutamate-receptor-mediated synaptic transmission was studied in morphologically identified hippocampal dentate granule cells (DGCs; n = 31) with the use of whole cell patch-clamp recording and intracellular injection of biocytin or Lucifer yellow in slices prepared from surgically removed medial temporal lobe specimens of epileptic patients (14 specimens from 14 patients). In the current-clamp recording, low-frequency stimulation of the perforant path generated depolarizing postsynaptic potentials that consisted of excitatory postsynaptic potentials and phase-inverted inhibitory postsynaptic potentials mediated by the γ-aminobutyric acid-A (GABAA) receptor at a resting membrane potential of −62.7 ± 2.0 (SE) mV. In the voltage-clamp recording, two glutamate conductances, a fast α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor-mediated excitatory postsynaptic current (EPSC; AMPA EPSC) and a slowly developing N-methyl-d-aspartate (NMDA)-receptor-mediated EPSC (NMDA EPSC), were isolated in the presence of a GABAA receptor antagonist. NMDA EPSCs showed a voltage-dependent increase in conductance with depolarization by exhibiting an N-shaped current-voltage relationship. The slope conductance of the NMDA EPSC ranged from 1.1 to 9.4 nS in 31 DGCs, reaching up to twice the size of the AMPA conductance. This widely varying size of the NMDA conductance resulted in the generation of double-peaked EPSCs and a nonlinear increase of the slope conductance of up to 37.5 nS with positive membrane potentials, which resembled “paroxysmal currents,” in a subpopulation of the neurons. In contrast, AMPA EPSCs, which were isolated in the presence of an NMDA receptor antagonist (2-amino-5-phosphonovaleric acid), showed voltage-independent linear changes in the current-voltage relationship and were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. The AMPA conductance showed little variance, regardless of the size of the NMDA conductance of a given neuron. The average AMPA slope conductance was 5.28 ± 0.65 (SE) nS in 31 human DGCs. This value was similar to AMPA EPSC conductances in normal rat DGCs (5.35 ± 0.52 nS, mean ± SE; n = 55). Dendritic morphology and spine density were quantified in the individual DGCs to assess epileptic pathology. Dendritic spine density showed an inverse correlation ( r 2 = 0.705) with a slower rise time and a longer half-width of the excitatory postsynaptic potentials mediated by the NMDA receptor. It is concluded that both AMPA and NMDA EPSCs contribute to human DGC synaptic transmission in epileptic hippocampus. However, a wide range of changes in the slope conductance of the NMDA EPSCs suggests that the NMDA-receptor-mediated conductance could be altered in human epileptic DGCs. These changes may influence the generation of chronic subthreshold epileptogenic synaptic activity and give rise to pathological excitation leading to epileptic seizures and dendritic pathology.

Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus

1996 ◽  
Vol 75 (5) ◽  
pp. 1901-1908 ◽  
Author(s):  
M. Isokawa
Keyword(s):  
Nmda Receptor ◽  
Granule Cells ◽  
Perforant Path ◽  
High Frequency Stimulation ◽  
Patch Clamp Recording ◽  
Dentate Granule Cells ◽  
Inhibitory Postsynaptic Currents ◽  
Postsynaptic Currents ◽  
Pilocarpine Model ◽  
Frequency Stimulation

1. Inhibitory postsynaptic currents (IPSCs) were studied in hippocampal dentate granule cells (DGCs) in the pilocarpine model and human temporal lobe epilepsy, with the use of the whole cell patch-clamp recording technique in slice preparations. 2. In the pilocarpine model, hippocampal slices were prepared from rats that were allowed to experience spontaneous seizures for 2 mo. Human hippocampal specimens were obtained from epileptic patients who underwent surgical treatment for medically intractable seizures. 3. IPSCs were generated by single perforant path stimulation and recorded at a membrane potential (Vm) of 0 mV near the reversal potential of glutamate excitatory postsynaptic currents in the voltage-clamp recording. IPSCs were pharmacologically identified as gamma-aminobutyric acid-A (GABAA) IPSCs by 10 microM bicuculline methiodide. 4. During low-frequency stimulation, IPSCs were not different in amplitude among non-seizure-experienced rat hippocampi, human nonsclerotic hippocampi, seizure-experienced rat hippocampi, and human sclerotic hippocampi. In the last two groups of DGCs, current-clamp recordings indicated the presence of prolonged excitatory postsynaptic potentials (EPSPs) mediated by the N-methyl-D-aspartate (NMDA) receptor. 5. High-frequency stimulation, administered at Vm = -30 mV to activate NMDA currents, reduced GABAA IPSC amplitude specifically in seizure-experienced rat hippocampi (t = 2.5, P < 0.03) and human sclerotic hippocampi (t = 7.7, P < 0.01). This reduction was blocked by an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV) (50 microM). The time for GABAA IPSCs to recover to their original amplitude was also shortened by the application of APV. 6. I conclude that, when intensively activated, NMDA receptor-mediated excitatory transmission may interact with GABAergic synaptic inhibition in DGCs in seizure-experienced hippocampus to transiently reduce GABA(A) receptor-channel function. Such interactions may contribute to give rise to epileptic excitation in chronically seizure-prone hippocampus.

scholarly journals Fate of Newborn Dentate Granule Cells after Early Life Status Epilepticus

Epilepsia ◽  
2004 ◽  
Vol 45 (1) ◽  
pp. 13-19 ◽  
Author(s):  
Brenda E. Porter ◽  
Margaret Maronski ◽  
Amy R. Brooks-Kayal
Keyword(s):  
Status Epilepticus ◽  
Early Life ◽  
Granule Cells ◽  
Dentate Granule Cells

NMDA-Dependent Currents in Granule Cells of the Dentate Gyrus Contribute to Induction but Not Permanence of Kindling

1999 ◽  
Vol 81 (2) ◽  
pp. 564-574 ◽  
Author(s):  
Ümit Sayin ◽  
Paul Rutecki ◽  
Thomas Sutula
Keyword(s):  
Nmda Receptor ◽  
Dentate Gyrus ◽  
Time Course ◽  
Granule Cells ◽  
Receptor Activation ◽  
Perforant Path ◽  
Synaptic Current ◽  
Synaptic Currents ◽  
Class V ◽  
Dependent Component

NMDA-dependent currents in granule cells of the dentate gyrus contribute to induction but not permanence of kindling. Single-electrode voltage-clamp techniques and bath application of the N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) were used to study the time course of seizure-induced alterations in NMDA-dependent synaptic currents in granule cells of the dentate gyrus in hippocampal slices from kindled and normal rats. In agreement with previous studies, granule cells from kindled rats examined within 1 wk after the last of 3 or 30–35 generalized tonic-clonic (class V) seizures demonstrated an increase in the NMDA receptor–dependent component of the perforant path–evoked synaptic current. Within 1 wk of the last kindled seizure, NMDA-dependent charge transfer underlying the perforant path–evoked current was increased by 63–111% at a holding potential of −30 mV. In contrast, the NMDA-dependent component of the perforant-evoked current in granule cells examined at 2.5–3 mo after the last of 3 or 90–120 class V seizures did not differ from age-matched controls. Because the seizure-induced increases in NMDA-dependent synaptic currents declined toward control values during a time course of 2.5–3 mo, increases in NMDA-dependent synaptic transmission cannot account for the permanent susceptibility to evoked and spontaneous seizures induced by kindling. The increase in NMDA receptor–dependent transmission was associated with the induction of kindling but was not responsible for the maintenance of the kindled state. The time course of alterations in NMDA-dependent synaptic current and the dependence of the progression of kindling and kindling-induced mossy fiber sprouting on repeated NMDA receptor activation are consistent with the possibility that the NMDA receptor is part of a transmembrane signaling pathway that induces long-term cellular alterations and circuit remodeling in response to repeated seizures, but is not required for permanent seizure susceptibility in circuitry altered by kindling.

scholarly journals NMDA Receptor-Dependent Plasticity of Granule Cell Spiking in the Dentate Gyrus of Normal and Epileptic Rats

2000 ◽  
Vol 84 (6) ◽  
pp. 2868-2879 ◽  
Author(s):  
M. Lynch ◽  
Ü. Sayin ◽  
G. Golarai ◽  
T. Sutula
Keyword(s):  
Nmda Receptor ◽  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Perforant Path ◽  
Spike Generation ◽  
Bathing Medium ◽  
Burst Discharge ◽  
Dependent Component ◽  
Single Spike

Because granule cells in the dentate gyrus provide a major synaptic input to pyramidal neurons in the CA3 region of the hippocampus, spike generation by granule cells is likely to have a significant role in hippocampal information processing. Granule cells normally fire in a single-spike mode even when inhibition is blocked and provide single-spike output to CA3 when afferent activity converging into the entorhinal cortex from neocortex, brainstem, and other limbic regions increases. The effects of enhancement of N-methyl-d-aspartate (NMDA) receptor-dependent excitatory synaptic transmission and reduction in γ-aminobutyric acid-A (GABAA) receptor-dependent inhibition on spike generation were examined in granule cells of the dentate gyrus. In contrast to the single-spike mode observed in normal bathing conditions, perforant path stimulation in Mg2+-free bathing conditions evoked graded burst discharges in granule cells which increased in duration, amplitude, and number of spikes as a function of stimulus intensity. After burst discharges were evoked during transient exposure to bathing conditions that relieve the Mg2+ block of the NMDA receptor, there was a marked increase in the NMDA receptor-dependent component of the EPSP, but no significant increase in the non-NMDA receptor-dependent component of the EPSP in normal bathing medium. Supramaximal perforant path stimulation still evoked only a single spike, but granule cell spike generation was immediately converted from a single-spike firing mode to a graded burst discharge mode when inhibition was then reduced. The induction of graded burst discharges in Mg2+-free conditions and the expression of burst discharges evoked in normal bathing medium with subsequent disinhibition were both blocked bydl-2-amino-4-phosphonovaleric acid (APV) and were therefore NMDA receptor dependent, in contrast to long-term potentiation (LTP) in the perforant path, which is induced by NMDA receptors and is also expressed by α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors. The graded burst discharge mode was also observed in granule cells when inhibition was reduced after a single epileptic afterdischarge, which enhances the NMDA receptor-dependent component of evoked synaptic response, and in the dentate gyrus reorganized by mossy fiber sprouting in kindled and kainic acid-treated rats. NMDA receptor-dependent plasticity of granule cell spike generation, which can be distinguished from LTP and induces long-term susceptibility to epileptic burst discharge under conditions of reduced inhibition, could modify information processing in the hippocampus and promote epileptic synchronization by increasing excitatory input into CA3.

PKA and PKC Enhance Excitatory Synaptic Transmission in Human Dentate Gyrus

2003 ◽  
Vol 89 (5) ◽  
pp. 2482-2488 ◽  
Author(s):  
Huan-Xin Chen ◽  
Steven N. Roper
Keyword(s):  
Protein Kinase ◽  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Phorbol Ester ◽  
Granule Cells ◽  
Excitatory Synaptic Transmission ◽  
Perforant Path ◽  
Short Term ◽  
Dentate Granule Cells ◽  
Presynaptic Mechanisms

cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) are two major modulators of synaptic transmission in the CNS but little is known about how they affect synaptic transmission in the human CNS. In this study, we used forskolin, a PKA activator, and phorbol ester, a PKC activator, to examine the effects of these kinases on synaptic transmission in granule cells of the dentate gyrus in human hippocampal slices using whole-cell recording methods. We found that both forskolin and phorbol ester increased the frequency of spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs) but left the amplitude unaffected. Inactive forskolin and phorbol ester had no effect on sEPSCs in human dentate granule cells. Prior application of forskolin occluded the effects of phorbol ester on mEPSC frequency. Tetanic stimulation applied to the perforant path induced short-term depression in dentate gyrus granule cells. Both forskolin and phorbol ester significantly enhanced this short-term depression. Taken together, these results demonstrate that PKA and PKC are involved in up-regulation of excitatory synaptic transmission in human dentate granule cells, primarily by presynaptic mechanisms. In addition, the occlusion experiments suggest that the two kinases may share a common signal pathway.

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 Dentate granule cells form novel basal dendrites in a rat model of temporal lobe epilepsy

Neuroscience ◽  
1998 ◽  
Vol 86 (1) ◽  
pp. 109-120 ◽  
Author(s):  
I Spigelman ◽  
X.-X Yan ◽  
A Obenaus ◽  
E.Y.-S Lee ◽  
C.G Wasterlain ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Rat Model ◽  
Granule Cells ◽  
Dentate Granule Cells ◽  
Basal Dendrites
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