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

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 Granule Cell Firing Rates Precede Locally Recorded Spontaneous Seizures by Minutes in an Animal Model of Temporal Lobe Epilepsy

Journal of Neurophysiology ◽

10.1152/jn.01369.2007 ◽

2008 ◽

Vol 99 (5) ◽

pp. 2431-2442 ◽

Cited By ~ 52

Author(s):

Mark R. Bower ◽

Paul S. Buckmaster

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Firing Rate ◽

Temporal Lobe ◽

Granule Cells ◽

Neuronal Firing ◽

Seizure Onset ◽

Electrographic Seizure ◽

Firing Rates ◽

Spontaneous Seizures

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

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.02.133 ◽

2012 ◽

Vol 420 (1) ◽

pp. 156-160 ◽

Cited By ~ 22

Author(s):

Rainer Surges ◽

Maria Kukley ◽

Amy Brewster ◽

Christiane Rüschenschmidt ◽

Johannes Schramm ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Cation Current

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Temporal Patterns of Fos Expression in the Dentate Gyrus after Spontaneous Seizures in a Mouse Model of Temporal Lobe Epilepsy

Journal of Neuroscience ◽

10.1523/jneurosci.0838-05.2005 ◽

2005 ◽

Vol 25 (31) ◽

pp. 7210-7220 ◽

Cited By ~ 62

Author(s):

Z. Peng

Keyword(s):

Mouse Model ◽

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Temporal Patterns ◽

Spontaneous Seizures ◽

Fos Expression

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Adaptive Intrinsic Plasticity in Human Dentate Gyrus Granule Cells during Temporal Lobe Epilepsy

Cerebral Cortex ◽

10.1093/cercor/bhr294 ◽

2011 ◽

Vol 22 (9) ◽

pp. 2087-2101 ◽

Cited By ~ 27

Author(s):

M. Stegen ◽

F. Kirchheim ◽

A. Hanuschkin ◽

O. Staszewski ◽

R. W. Veh ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Intrinsic Plasticity

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Optical Recording Study of Granule Cell Activities in the Hippocampal Dentate Gyrus of Kainate-Treated Rats

Journal of Neurophysiology ◽

10.1152/jn.2000.83.4.2421 ◽

2000 ◽

Vol 83 (4) ◽

pp. 2421-2430 ◽

Cited By ~ 12

Author(s):

Yo Otsu ◽

Eiichi Maru ◽

Hisayuki Ohata ◽

Ichiro Takashima ◽

Riichi Kajiwara ◽

...

Keyword(s):

Dentate Gyrus ◽

Granule Cell ◽

Granule Cells ◽

Mossy Fiber ◽

Molecular Layer ◽

Mossy Fibers ◽

Optical Recording ◽

Granule Cell Layer ◽

Gabaergic Inhibition ◽

Mossy Fiber Sprouting

In the epileptic hippocampus, newly sprouted mossy fibers are considered to form recurrent excitatory connections to granule cells in the dentate gyrus and thereby increase seizure susceptibility. To study the effects of mossy fiber sprouting on neural activity in individual lamellae of the dentate gyrus, we used high-speed optical recording to record signals from voltage-sensitive dye in hippocampal slices prepared from kainate-treated epileptic rats (KA rats). In 14 of 24 slices from KA rats, hilar stimulation evoked a large depolarization in almost the entire molecular layer in which granule cell apical dendrites are located. The signals were identified as postsynaptic responses because of their dependence on extracellular Ca2+. The depolarization amplitude was largest in the inner molecular layer (the target area of sprouted mossy fibers) and declined with increasing distance from the granule cell layer. In the inner molecular layer, a good correlation was obtained between depolarization size and the density of mossy fiber terminals detected by Timm staining methods. Blockade of GABAergic inhibition by bicuculline enlarged the depolarization in granule cell dendrites. Our data indicate that mossy fiber sprouting results in a large and prolonged synaptic depolarization in an extensive dendritic area and that the enhanced GABAergic inhibition partly masks the synaptic depolarization. However, despite the large dendritic excitation induced by the sprouted mossy fibers, seizurelike activity of granule cells was never observed, even when GABAergic inhibition was blocked. Therefore, mossy fiber sprouting may not play a critical role in epileptogenesis.

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Altered synaptic transmission in dentate gyrus of rats reared in complex environments: evidence from hippocampal slices maintained in vitro

Journal of Neurophysiology ◽

10.1152/jn.1986.55.4.739 ◽

1986 ◽

Vol 55 (4) ◽

pp. 739-750 ◽

Cited By ~ 123

Author(s):

E. J. Green ◽

W. T. Greenough

Keyword(s):

Synaptic Transmission ◽

Dentate Gyrus ◽

Granule Cell ◽

Granule Cells ◽

Cell Layer ◽

Molecular Layer ◽

Hippocampal Slices ◽

Granule Cell Layer ◽

Complex Environments ◽

Rearing Environment

Pre- and postsynaptic responses to activation of medial perforant path (MPP) axons were examined in hippocampal slices taken from rats reared for 3-4 wk in relatively complex (EC) or individual cage (IC) environments. Three types of extracellular field potentials were recorded in the infrapyramidal blade of the dentate gyrus: 1) granule cell population spikes (PSs), which reflect the number and synchrony of discharging granule cells (2), 2) population excitatory postsynaptic potentials (EPSPs), which reflect the amount of excitatory synaptic current flow into dendrites (28), and 3) presynaptic fiber volleys (FVs), which reflect the number of activated axons (28). Stimulation of the MPP evoked significantly larger PSs in slices taken from EC rats. There was no significant effect of rearing environment on PS/EPSP relationships. The slopes of EPSPs recorded at the site of synaptic activation in the dentate molecular layer and at the major current source in the dentate granule cell layer were significantly greater in slices taken from EC rats. The presynaptic FV was recorded at the site of synaptic activation in the molecular layer. FV amplitude did not differ significantly as a function of rearing environment. To examine possible differences in tissue impedance, granule cells were activated by stimulating granule cell axons in the dentate hilus and recording the antidromic PS in the granule cell layer. Antidromic PS amplitude was not significantly affected by rearing environment. The relative permanence of the experience-dependent alterations in synaptic transmission was assessed by comparing slices taken from rats that had been reared for 4 wk in complex environments followed by 3-4 wk in individual cages with those from rats reared for 7-8 wk in individual cages. There were no significant differences in MPP synaptic transmission between these groups of animals. The results suggest that experience in a relatively complex environment is associated with greater MPP synaptic transmission arising from an increased synaptic input to granule cells; the greater MPP synaptic transmission associated with behavioral experience can occur independent of behavioral state, influences from extrahippocampal brain regions and intrahippocampal inhibitory activity; and the experience-dependent synaptic alterations in the dentate gyrus are transient, in contrast to experience-dependent morphological alterations described in occipital cortex. The possible relationship of these alterations to the phenomenon of long-term enhancement is discussed.

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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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Intrinsic neurophysiological properties of hilar ectopic and normotopic dentate granule cells in human temporal lobe epilepsy and a rat model

Journal of Neurophysiology ◽

10.1152/jn.00835.2014 ◽

2015 ◽

Vol 113 (4) ◽

pp. 1184-1194 ◽

Cited By ~ 25

Author(s):

A. L. Althaus ◽

O. Sagher ◽

J. M. Parent ◽

G. G. Murphy

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Granule Cells ◽

Salient Feature ◽

Granule Cell Layer ◽

Disease Stage ◽

Resting Membrane Potential ◽

Firing Rates ◽

Dentate Granule Cells ◽

Human Temporal Lobe

Hilar ectopic dentate granule cells (DGCs) are a salient feature of aberrant plasticity in human temporal lobe epilepsy (TLE) and most rodent models of the disease. Recent evidence from rodent TLE models suggests that hilar ectopic DGCs contribute to hyperexcitability within the epileptic hippocampal network. Here we investigate the intrinsic excitability of DGCs from humans with TLE and the rat pilocarpine TLE model with the objective of comparing the neurophysiology of hilar ectopic DGCs to their normotopic counterparts in the granule cell layer (GCL). We recorded from 36 GCL and 7 hilar DGCs from human TLE tissue. Compared with GCL DGCs, hilar DGCs in patient tissue exhibited lower action potential (AP) firing rates, more depolarized AP threshold, and differed in single AP waveform, consistent with an overall decrease in excitability. To evaluate the intrinsic neurophysiology of hilar ectopic DGCs, we made recordings from retrovirus-birthdated, adult-born DGCs 2–4 mo after pilocarpine-induced status epilepticus or sham treatment in rats. Hilar DGCs from epileptic rats exhibited higher AP firing rates than normotopic DGCs from epileptic or control animals. They also displayed more depolarized resting membrane potential and wider AP waveforms, indicating an overall increase in excitability. The contrasting findings between disease and disease model may reflect differences between the late-stage disease tissue available from human surgical specimens and the earlier disease stage examined in the rat TLE model. These data represent the first neurophysiological characterization of ectopic DGCs from human hippocampus and prospectively birthdated ectopic DGCs in a rodent TLE model.

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