Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy

Although much is known about persistent molecular, cellular, and circuit changes associated with temporal lobe epilepsy, mechanisms of seizure onset remain unclear. The dentate gyrus displays many persistent epilepsy-related abnormalities and is in the mesial temporal lobe where seizures initiate in patients. However, little is known about seizure-related activity of individual neurons in the dentate gyrus. We used tetrodes to record action potentials of multiple, single granule cells before and during spontaneous seizures in epileptic pilocarpine-treated rats. Subsets of granule cells displayed four distinct activity patterns: increased firing before seizure onset, decreased firing before seizure onset, increased firing only after seizure onset, and unchanged firing rates despite electrographic seizure activity in the immediate vicinity. No cells decreased firing rate immediately after seizure onset. During baseline periods between seizures, action potential waveforms and firing rates were similar among the four subsets of granule cells in epileptic rats and in granule cells of control rats. The mean normalized firing rate of granule cells whose firing rates increased before seizure onset deviated from baseline earliest, beginning 4 min before dentate gyrus electrographic seizure onset, and increased progressively, more than doubling by seizure onset. It is generally assumed that neuronal firing rates increase abruptly and synchronously only when electrographic seizures begin. However, these findings show heterogeneous and gradually building changes in activity of individual granule cells minutes before spontaneous seizures.

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Correlation between calbindin expression in granule cells of the resected hippocampal dentate gyrus and verbal memory in temporal lobe epilepsy

Epilepsy & Behavior ◽

10.1016/j.yebeh.2012.06.007 ◽

2012 ◽

Vol 25 (1) ◽

pp. 110-119 ◽

Cited By ~ 16

Author(s):

Kázmér Karádi ◽

József Janszky ◽

Csilla Gyimesi ◽

Zsolt Horváth ◽

Tivadar Lucza ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Verbal Memory ◽

Granule Cells ◽

Hippocampal Dentate Gyrus

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Upregulation of inward rectifier K+(Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy

The Journal of Physiology ◽

10.1113/jphysiol.2009.170746 ◽

2009 ◽

Vol 587 (17) ◽

pp. 4213-4233 ◽

Cited By ~ 43

Author(s):

Christina C. Young ◽

Michael Stegen ◽

René Bernard ◽

Martin Müller ◽

Josef Bischofberger ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Inward Rectifier

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Hippocampal Transplants of Fetal GABAergic Progenitors Regulate Adult Neurogenesis in Mice with Temporal Lobe Epilepsy

10.1101/2022.01.11.475674 ◽

2022 ◽

Author(s):

Muhammad Nauman Arshad ◽

Simon Oppenheimer ◽

Jaye Jeong ◽

Bilge Buyukdemirtas ◽

Janice R Naegele

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Adult Neurogenesis ◽

Granule Cell ◽

Granule Cells ◽

Granule Cell Layer ◽

Spontaneous Seizures ◽

Type 3

GABAergic interneurons within the dentate gyrus of the hippocampus regulate adult neurogenesis, including proliferation, migration, and maturation of new granule cells born in the subgranular zone (SGZ) of the dentate gyrus (DG). In temporal lobe epilepsy (TLE), some adult-born granule cells migrate ectopically into the hilus, and these cells contribute to increased hyperexcitability and seizures. Yet, transplanting embryonic day 13.5 fetal mouse medial ganglionic eminence (MGE) GABAergic progenitors into the hippocampus of mice with TLE ameliorates spontaneous seizures, due in part, to increased postsynaptic inhibition of adult-born granule cells. Here, we asked whether MGE progenitor transplantation affects earlier stages of adult neurogenesis, by comparing patterns of neurogenesis in naive mice and epileptic (TLE) mice, with or without MGE transplants. In naive and TLE mice, transplanted MGE cells showed comparable migration and process outgrowth. However, in TLE mice with MGE transplants, fewer adult-born Type 3 progenitors migrated ectopically. Furthermore, more Type 3 progenitors survived and migrated into the granule cell layer (GCL), as determined by immunostaining for doublecortin or the thymidine analogue, bromodeoxyuridine (BrdU). To determine whether MGE transplants affected earlier stages of adult neurogenesis, we compared proliferation in the SGZ two-hours after pulse labeling with BrdU in naive vs. TLE mice and found no significant differences. Furthermore, MGE progenitor transplantation had no effect on cell proliferation in the SGZ. Moreover, when compared to naive mice, TLE mice showed increases in inverted Type 1 progenitors and Type 2 progenitors, concomitant with a decrease in the normally oriented radial Type 1 progenitors. Strikingly, these alterations were abrogated by MGE transplantation. Thus, MGE transplants appear to reverse seizure-induced abnormalities in adult neurogenesis by increasing differentiation and radial migration of adult-born granule cell progenitors, outcomes that may ameliorate seizures.

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Changes in inhibitory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy

Journal of Neurophysiology ◽

10.1152/jn.1995.74.2.829 ◽

1995 ◽

Vol 74 (2) ◽

pp. 829-840 ◽

Cited By ~ 35

Author(s):

P. S. Mangan ◽

D. A. Rempe ◽

E. W. Lothman

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Pyramidal Cells ◽

Stratum Radiatum ◽

Ca1 Pyramidal Cells ◽

Ca1 Region ◽

Stratum Lacunosum Moleculare ◽

Reversal Potentials

1. In this report we compare changes in inhibitory neurotransmission within the CA1 region and the dentate gyrus (DG) in a model of chronic temporal lobe epilepsy (TLE). Extracellular and intracellular recordings were obtained in combined hippocampal-parahippocampal slices > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 2. Polysynaptic inhibitory postsynaptic potentials (IPSPs) were induced by positioning electrodes to activate specific afferent pathways and evoking responses in the absence of glutamate receptor antagonists [D(-)-2-amino-5-phosphonovaleric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)]. Polysynaptic IPSPs were evoked in CA1 pyramidal cells from electrodes positioned in stratum radiatum and in stratum lacunosum/moleculare. Polysynaptic IPSPs were evoked in DG granule cells from electrodes positioned over the perforant path located in the subiculum. Monosynaptic IPSPs were induced by positioning electrodes within 200 microns of the intracellular recording electrode (near site stimulation) and stimulating in the presence of APV and CNQX to block ionotropic glutamate receptors. Monosynaptic IPSPs were evoked in CA1 pyramidal cells with electrodes positioned in the stratum lacunosum/moleculare and stratum pyramidale. Monosynaptic IPSPs were evoked in DG granule cells with electrodes positioned in the stratum moleculare. 3. Population spike (PS) amplitudes were employed to assure that a full range of stimulus strengths, from subthreshold for action potentials to an intensity giving maximal-amplitude PSs, was used to elicit polysynaptic IPSPs in CA1 pyramidal cells in both post-SSLSE and control slices. In control tissue, polysynaptic IPSPs were biphasic, composed of early and late events. In post-SSLSE tissue, polysynaptic IPSPs were markedly diminished. The diminution of polysynaptic IPSPs was detected at all levels of stimulus intensity. Both early IPSPs [mediated by gamma-aminobutyric acid-A (GABAA) receptors] and late IPSPs (mediated by GABAB receptors) were diminished. Polysynaptic IPSPs were diminished with both stratum radiatum and with stratum lacunosum/moleculare stimulation. 4. Reversal potentials for either polysynaptic early or polysynaptic late IPSPs evoked in CA1 pyramidal cells by stratum radiatum stimulation were not different in slices from post-SSLSE animals as compared with control animals. Likewise, reversal potentials for either polysynaptic early or polysynaptic late IPSPs evoked by stratum lacunosum/moleculare stimulation did not differ in the two groups. These findings excluded changes in driving force as an explanation for the diminished amplitude of IPSPs in CA1 pyramidal cells in the post-SSLSE model.(ABSTRACT TRUNCATED AT 400 WORDS)

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Circuit-based interventions in the dentate gyrus rescue epilepsy-associated cognitive dysfunction

Brain ◽

10.1093/brain/awz209 ◽

2019 ◽

Vol 142 (9) ◽

pp. 2705-2721 ◽

Cited By ~ 6

Author(s):

Julia B Kahn ◽

Russell G Port ◽

Cuiyong Yue ◽

Hajime Takano ◽

Douglas A Coulter

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Cognitive Dysfunction ◽

Temporal Lobe ◽

Granule Cell ◽

Granule Cells ◽

Dorsal Hippocampus ◽

Cell Activity ◽

Downstream Target ◽

Behavioural Performance

Abstract Temporal lobe epilepsy is associated with significant structural pathology in the hippocampus. In the dentate gyrus, the summative effect of these pathologies is massive hyperexcitability in the granule cells, generating both increased seizure susceptibility and cognitive deficits. To date, therapeutic approaches have failed to improve the cognitive symptoms in fully developed, chronic epilepsy. As the dentate’s principal signalling population, the granule cells’ aggregate excitability has the potential to provide a mechanistically-independent downstream target. We examined whether normalizing epilepsy-associated granule cell hyperexcitability—without correcting the underlying structural circuit disruptions—would constitute an effective therapeutic approach for cognitive dysfunction. In the systemic pilocarpine mouse model of temporal lobe epilepsy, the epileptic dentate gyrus excessively recruits granule cells in behavioural contexts, not just during seizure events, and these mice fail to perform on a dentate-mediated spatial discrimination task. Acutely reducing dorsal granule cell hyperactivity in chronically epileptic mice via either of two distinct inhibitory chemogenetic receptors rescued behavioural performance such that they responded comparably to wild type mice. Furthermore, recreating granule cell hyperexcitability in control mice via excitatory chemogenetic receptors, without altering normal circuit anatomy, recapitulated spatial memory deficits observed in epileptic mice. However, making the granule cells overly quiescent in both epileptic and control mice again disrupted behavioural performance. These bidirectional manipulations reveal that there is a permissive excitability window for granule cells that is necessary to support successful behavioural performance. Chemogenetic effects were specific to the targeted dorsal hippocampus, as hippocampal-independent and ventral hippocampal-dependent behaviours remained unaffected. Fos expression demonstrated that chemogenetics can modulate granule cell recruitment via behaviourally relevant inputs. Rather than driving cell activity deterministically or spontaneously, chemogenetic intervention merely modulates the behaviourally permissive activity window in which the circuit operates. We conclude that restoring appropriate principal cell tuning via circuit-based therapies, irrespective of the mechanisms generating the disease-related hyperactivity, is a promising translational approach.

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Changes in excitatory neurotransmission in the CA1 region and dentate gyrus in a chronic model of temporal lobe epilepsy

Journal of Neurophysiology ◽

10.1152/jn.1995.74.2.841 ◽

1995 ◽

Vol 74 (2) ◽

pp. 841-848 ◽

Cited By ~ 39

Author(s):

E. W. Lothman ◽

D. A. Rempe ◽

P. S. Mangan

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Pyramidal Cells ◽

Postsynaptic Potentials ◽

Ca1 Pyramidal Cells ◽

Control Tissue ◽

Ca1 Region ◽

Excitatory Neurotransmission

1. In this report we compare changes of excitatory neurotransmission within the CA1 region and the dentate gyrus (DG) in a model of chronic temporal lobe epilepsy (TLE). Extracellular and intracellular recordings were obtained from in vitro hippocampal-parahippocampal slices > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. Pyramidal cells in CA1 were activated by electrodes in the stratum lacunosum/moleculare or stratum radiatum. Granule cells in DG were similarly activated by electrodes positioned in the perforant path. 2. Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in CA1 pyramidal cells in post-SSLSE tissue were always longer than those evoked in control tissue, irrespective of whether hyperresponsiveness was present or not. EPSPs elicited by stimulus subthreshold for action potentials (APs) in post-SSLSE and in control slices and matched in amplitude had a statistically greater duration in the post-SSLSE slices. Durations of monosynaptic EPSPs elicited by stimuli subthreshold for APs in DG granule cells in post-SSLSE slices were not longer than EPSPs of equal amplitude elicited in control slices. 3. Higher-intensity stimuli produced EPSPs with associated APs and, in certain cases in the post-SSLSE tissue, hyperresponsive events with multiple (> or = 3) APs. Durations of depolarizing profiles with stimuli producing APs were overall longer in both CA1 pyramidal cells and DG granule cells and correlated with the degree of hyperresponsiveness. 4. Neither the amplitudes nor the durations of monosynaptic EPSPs evoked in CA1 pyramidal cells in slices from control animals were affected by the addition of D(-)-2-amino-5-phosphonovaleric acid (APV), a blocker of the N-methyl-D-aspartate (NMDA) receptor, to the artificial cerebrospinal fluid (ACSF) bathing the slices. In contrast to the situation in control tissue, in post-SSLSE tissue APV shortened EPSPs evoked in CA1 pyramidal cells while not changing their amplitudes. After APV, inhibitory postsynaptic potentials (IPSPs) remained greatly diminished or absent in CA1 pyramidal cells. APV did not statistically decrease amplitudes of monosynaptic EPSPs evoked in DG granule cells in either control slices or post-SSLSE slices. APV decreased EPSP durations in both types of slices, more so in the post-SSLSE tissue. 5. In control slices, APV did not change the amplitudes or durations of depolarizing profiles of responses evoked by stimuli producing APs in CA1. Similarly, APV did not change the amplitudes of such responses in DG. However, APV did reduce the durations of such responses in DG in control slices.(ABSTRACT TRUNCATED AT 400 WORDS)

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Increased leak conductance in dentate gyrus granule cells of temporal lobe epilepsy patients with Ammon’s horn sclerosis

Epilepsia ◽

10.1111/j.1528-1167.2009.02025.x ◽

2009 ◽

Vol 50 (4) ◽

pp. 646-653 ◽

Cited By ~ 22

Author(s):

Michael Stegen ◽

Christina C. Young ◽

Carola A. Haas ◽

Josef Zentner ◽

Jakob Wolfart

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Ammon's Horn ◽

Ammon's Horn Sclerosis ◽

Ammon’S Horn ◽

Ammon’S Horn Sclerosis

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Impacted Spike Frequency Adaptation Associated with Reduction of KCNQ2/3 Promotes Seizure Activity in Temporal Lobe Epilepsy

10.1101/2020.09.25.313254 ◽

2020 ◽

Author(s):

Rongrong Li ◽

Shicheng Jiang ◽

Shuo Tan ◽

Bei Liu ◽

Yang Liu ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Neuronal Excitability ◽

Granule Cells ◽

Epileptiform Activity ◽

Spike Frequency ◽

Small Scale ◽

Spike Frequency Adaptation ◽

Frequency Adaptation

ABSTRACTAlthough numerous epilepsy-related genes have been identified by unbiased genome-wide screening based on samples from both animal models and patients, the druggable targets for temporal lobe epilepsy (TLE) are still limited. Meanwhile, a large number of candidate genes that might promote or inhibit seizure activities are waiting for further validation. In this study, we first analyzed two public databases and determined the significant down-regulations of two M-type potassium channel genes (KCNQ2/3) expressions in hippocampus samples from TLE patients. Then we reproduced the similar pathological changes in the pilocarpine mouse model of TLE and further detected the decrease of spike frequency adaptation driven by impacted M-currents on dentate gyrus granule neurons. Finally, we employed a small-scale simulation of dentate gyrus network to investigate potential functional consequences of disrupted neuronal excitability. We demonstrated that the impacted spike frequency adaptation of granule cells facilitated the epileptiform activity among the entire network, including prolonged seizure duration and reduced interictal intervals. Our results identify a new mechanism contributing to ictogenesis in TLE and suggest a novel target for the anti-epileptic drug discovery.

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