scholarly journals Melatonin Influences Structural Plasticity in the Axons of Granule Cells in the Dentate Gyrus of Balb/C Mice

2018 ◽  
Vol 20 (1) ◽  
pp. 73 ◽  
Author(s):  
Gerardo Ramírez-Rodríguez ◽  
Sandra Olvera-Hernández ◽  
Nelly Vega-Rivera ◽  
Leonardo Ortiz-López
Keyword(s):  
Dentate Gyrus ◽  
Calcium Binding ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Structural Plasticity ◽  
Granular Cell ◽  
Newborn Neurons ◽  
The Impact ◽  
Ca3 Region

Melatonin, the main product synthesized by the pineal gland, acts as a regulator of the generation of new neurons in the dentate gyrus (DG). Newborn neurons buffer the deleterious effects of stress and are involved in learning and memory processes. Furthermore, melatonin, through the regulation of the cytoskeleton, favors dendrite maturation of newborn neurons. Moreover, newborn neurons send their axons via the mossy fiber tract to Cornu Ammonis 3 (CA3) region to form synapses with pyramidal neurons. Thus, axons of newborn cells contribute to the mossy fiber projection and their plasticity correlates with better performance in several behavioral tasks. Thus, in this study, we analyzed the impact of exogenous melatonin (8 mg/kg) administered daily for one- or six-months on the structural plasticity of infrapyramidal- and suprapyramidal mossy fiber projection of granule cells in the DG in male Balb/C mice. We analyzed the mossy fiber projection through the staining of calbindin, that is a calcium-binding protein localized in dendrites and axons. We first found an increase in the number of calbindin-positive cells in the granular cell layer in the DG (11%, 33%) after treatment. Futhermore, we found an increase in the volume of suprapyramidal (>135%, 59%) and infrapyramidal (>128%, 36%) mossy fiber projection of granule neurons in the DG after treatment. We also found an increase in the volume of CA3 region (>146%, 33%) after treatment, suggesting that melatonin modulates the structural plasticity of the mossy fiber projection to establish functional synapses in the hippocampus. Together, the data suggest that, in addition to the previously reported effects of melatonin on the generation of new neurons and its antidepressant like effects, melatonin also modulates the structural plasticity of axons in granule cells in the DG.

scholarly journals Regionally Localized Recurrent Excitation in the Dentate Gyrus of a Cortical Contusion Model of Posttraumatic Epilepsy

2010 ◽  
Vol 103 (3) ◽  
pp. 1490-1500 ◽  
Author(s):  
Robert F. Hunt ◽  
Stephen W. Scheff ◽  
Bret N. Smith
Keyword(s):  
Head Injury ◽  
Dentate Gyrus ◽  
Action Potentials ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Granule Cell Layer ◽  
Mossy Fiber Sprouting ◽  
Posttraumatic Epilepsy ◽  
Dentate Granule Cells ◽  
Cortical Contusion

Posttraumatic epilepsy is a frequent consequence of brain trauma, but relatively little is known about how neuronal circuits are chronically altered after closed head injury. We examined whether local recurrent excitatory synaptic connections form between dentate granule cells in mice 8–12 wk after cortical contusion injury. Mice were monitored for behavioral seizures shortly after brain injury and ≤10 wk postinjury. Injury-induced seizures were observed in 15% of mice, and spontaneous seizures were observed weeks later in 40% of mice. Timm's staining revealed mossy fiber sprouting into the inner molecular layer of the dorsal dentate gyrus ipsilateral to the injury in 95% of mice but not contralateral to the injury or in uninjured controls. Whole cell patch-clamp recordings were made from granule cells in isolated hippocampal brain slices. Cells in slices with posttraumatic mossy fiber sprouting had an increased excitatory postsynaptic current (EPSC) frequency compared with cells in slices without sprouting from injured and control animals ( P < 0.001). When perfused with Mg2+-free artificial cerebrospinal fluid containing 100 μM picrotoxin, these cells had spontaneous bursts of EPSCs and action potentials. Focal glutamate photostimulation of the granule cell layer evoked a burst of EPSCs and action potentials indicative of recurrent excitatory connections in granule cells of slices with mossy fiber sprouting. In granule cells of slices without sprouting from injured animals and controls, spontaneous or photostimulation-evoked epileptiform activity was never observed. These results suggest that a new regionally localized excitatory network forms between dentate granule cells near the injury site within weeks after cortical contusion head injury.

Mossy Fiber–Granule Cell Synapses in the Normal and Epileptic Rat Dentate Gyrus Studied With Minimal Laser Photostimulation

1999 ◽  
Vol 82 (4) ◽  
pp. 1883-1894 ◽  
Author(s):  
Péter Molnár ◽  
J. Victor Nadler
Keyword(s):  
Status Epilepticus ◽  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Hippocampal Formation ◽  
Control Groups ◽  
Small Component ◽  
Fiber Growth ◽  
And Control

Dentate granule cells become synaptically interconnected in the hippocampus of persons with temporal lobe epilepsy, forming a recurrent mossy fiber pathway. This pathway may contribute to the development and propagation of seizures. The physiology of mossy fiber–granule cell synapses is difficult to characterize unambiguously, because electrical stimulation may activate other pathways and because there is a low probability of granule cell interconnection. These problems were addressed by the use of scanning laser photostimulation in slices of the caudal hippocampal formation. Glutamate was released from a caged precursor with highly focused ultraviolet light to evoke action potentials in a small population of granule cells. Excitatory synaptic currents were recorded in the presence of bicuculline. Minimal laser photostimulation evoked an apparently unitary excitatory postsynaptic current (EPSC) in 61% of granule cells from rats that had experienced pilocarpine-induced status epilepticus followed by recurrent mossy fiber growth. An EPSC was also evoked in 13–16% of granule cells from the control groups. EPSCs from status epilepticus and control groups had similar peak amplitudes (∼30 pA), 20–80% rise times (∼1.2 ms), decay time constants (∼10 ms), and half-widths (∼8 ms). The mean failure rate was high (∼70%) in both groups, and in both groups activation of N-methyl-d-aspartate receptors contributed a small component to the EPSC. The strong similarity between responses from the status epilepticus and control groups suggests that they resulted from activation of a similar synaptic population. No EPSC was recorded when the laser beam was focused in the dentate hilus, suggesting that indirect activation of hilar mossy cells contributed little, if at all, to these results. Recurrent mossy fiber growth increases the density of mossy fiber–granule cell synapses in the caudal dentate gyrus by perhaps sixfold, but the new synapses appear to operate very similarly to preexisting mossy fiber–granule cell synapses.

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

2000 ◽  
Vol 83 (4) ◽  
pp. 2421-2430 ◽  
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.

scholarly journals Changes in TrkB–ERK1/2–CREB/Elk-1 Pathways in Hippocampal Mossy Fiber Organization after Traumatic Brain Injury

2004 ◽  
Vol 24 (8) ◽  
pp. 934-943 ◽  
Author(s):  
Bingren Hu ◽  
Chunli Liu ◽  
Helen Bramlett ◽  
Thomas J. Sick ◽  
Ofelia F. Alonso ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Dentate Gyrus ◽  
Signaling Pathways ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Control Level ◽  
Mossy Fibers ◽  
Underlying Mechanism ◽  
Fiber Organization

Traumatic brain injury (TBI) leads to mossy fiber reorganization, which is considered to be a causative factor in the development of temporal lobe epilepsy. However, the underlying mechanism is not fully understood. Emerging evidence suggests that TrkB–ERK1/2–CREB/Elk-1 pathways are highly related to synaptic plasticity. This study used the rat fluid-percussion injury model to investigate activation of TrkB–ERK1/2–CREB/Elk-1 signaling pathways after TBI. Rats were subjected to 2.0-atm parasagittal TBI followed by 30 minutes, 4 hours, 24 hours, and 72 hours of recovery. After TBI, striking activation of TrkB–ERK1/2–CREB/Elk-1 signaling pathways in mossy fiber organization were observed with confocal microscopy and Western blot analysis. ERK1/2 was highly phosphorylated predominantly in hippocampal mossy fibers, whereas TrkB was phosphorylated both in the mossy fibers and the dentate gyrus region at 30 minutes and 4 hours of recovery after TBI. CREB was also activated at 30 minutes, peaked at 24 hours of recovery, and returned to the control level at 72 hours of recovery in dentate gyrus granule cells. Elk-1 phosphorylation was seen in CA3 neurons at 4 hours after TBI. The results suggest that the signaling pathways of TrkB–ERK1/2–CREB/Elk-1 are highly activated in mossy fiber organization, which may contribute to mossy fiber reorganization seen after TBI.

scholarly journals Adult dentate gyrus neurogenesis: a functional model

2019 ◽  
Author(s):  
Olivia Gozel ◽  
Wulfram Gerstner
Keyword(s):  
Theoretical Model ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Functional Integration ◽  
Functional Model ◽  
Behavioral Pattern ◽  
Pattern Separation ◽  
Cell Maturation ◽  
Newborn Cell ◽  
Newborn Neurons

SummaryIn adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells towards stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.

scholarly journals Heterogeneities in afferent connectivity dominate local heterogeneities in the emergence of response decorrelation in the dentate gyrus

2017 ◽  
Author(s):  
Poonam Mishra ◽  
Rishikesh Narayanan
Keyword(s):  
Olfactory Bulb ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Information Transfer ◽  
Granule Cells ◽  
Dominant Role ◽  
Critical Role ◽  
Local Network ◽  
Afferent Inputs ◽  
The Impact

ABSTRACTThe ability of a neuronal population to effectuate response decorrelation has been identified as an essential prelude to efficient neural encoding. To what extent are diverse forms of local and afferent heterogeneities essential in accomplishing such response decorrelation in the dentate gyrus (DG)? Here, we incrementally incorporated four distinct forms of biological heterogeneities into conductance-based network models of the DG and systematically delineate their relative contributions to response decorrelation. We incorporated intrinsic heterogeneities by stochastically generating several electrophysiologically-validated basket and granule cell models that exhibited significant parametric variability, and introduced synaptic heterogeneities through randomized local synaptic strengths. In including adult neurogenesis, we subjected the valid model populations to randomized structural plasticity and matched neuronal excitability to electrophysiological data. We assessed networks comprising different combinations of these three local heterogeneities with identical or heterogeneous afferent inputs from the entorhinal cortex. We found that the three forms of local heterogeneities were independently and synergistically capable of mediating significant response decorrelation when the network was driven by identical afferent inputs. Strikingly, however, when we incorporated afferent heterogeneities into the network to account for the unique divergence in DG afferent connectivity, the impact of all three forms of local heterogeneities were significantly suppressed by the dominant role of afferent heterogeneities in mediating response decorrelation. Our results unveil a unique convergence of cellular- and network-scale degeneracy in the emergence of response decorrelation in the DG, and constitute a significant departure from the literature that assigns a critical role for local network heterogeneities in input discriminability.SIGNIFICANCE STATEMENTThe olfactory bulb and the dentate gyrus (DG) networks assimilate new neurons in adult rodents, with adult neurogenesis postulated to subserve efficacious information transfer by reducing correlations in neuronal responses to afferent inputs. Heterogeneities emerging from the lateral dendro-dendritic synapses, mediated by locally-projecting neurogenic inhibitory granule cells, are known to play critical roles in channel decorrelation in the olfactory bulb. However, the contributions of different heterogeneities in mediating response decorrelation in DG, comprising neurogenic excitatory granule cells projecting beyond DG and endowed with uniquely divergent afferent inputs, have not been delineated. Here, we quantitatively demonstrate the dominance of afferent heterogeneities, over multiple local heterogeneities, in the emergence of response decorrelation in DG, together unveiling cross-region degeneracy in accomplishing response decorrelation.

Recurrent Mossy Fiber Pathway in Rat Dentate Gyrus: Synaptic Currents Evoked in Presence and Absence of Seizure-Induced Growth

1999 ◽  
Vol 81 (4) ◽  
pp. 1645-1660 ◽  
Author(s):  
Maxine M. Okazaki ◽  
Péter Molnár ◽  
J. Victor Nadler
Keyword(s):  
Status Epilepticus ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Molecular Layer ◽  
Mossy Fibers ◽  
Fiber Growth ◽  
Antidromic Stimulation ◽  
Mossy Fiber Pathway ◽  
Stimulation Of

Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. A common feature of temporal lobe epilepsy and of animal models of epilepsy is the growth of hippocampal mossy fibers into the dentate molecular layer, where at least some of them innervate granule cells. Because the mossy fibers are axons of granule cells, the recurrent mossy fiber pathway provides monosynaptic excitatory feedback to these neurons that could facilitate seizure discharge. We used the pilocarpine model of temporal lobe epilepsy to study the synaptic responses evoked by activating this pathway. Whole cell patch-clamp recording demonstrated that antidromic stimulation of the mossy fibers evoked an excitatory postsynaptic current (EPSC) in ∼74% of granule cells from rats that had survived >10 wk after pilocarpine-induced status epilepticus. Recurrent mossy fiber growth was demonstrated with the Timm stain in all instances. In contrast, antidromic stimulation of the mossy fibers evoked an EPSC in only 5% of granule cells studied 4–6 days after status epilepticus, before recurrent mossy fiber growth became detectable. Notably, antidromic mossy fiber stimulation also evoked an EPSC in many granule cells from control rats. Clusters of mossy fiber-like Timm staining normally were present in the inner third of the dentate molecular layer at the level of the hippocampal formation from which slices were prepared, and several considerations suggested that the recorded EPSCs depended mainly on activation of recurrent mossy fibers rather than associational fibers. In both status epilepticus and control groups, the antidromically evoked EPSC was glutamatergic and involved the activation of both AMPA/kainate and N-methyl-d-aspartate (NMDA) receptors. EPSCs recorded in granule cells from rats with recurrent mossy fiber growth differed in three respects from those recorded in control granule cells: they were much more frequently evoked, a number of them were unusually large, and the NMDA component of the response was generally much more prominent. In contrast to the antidromically evoked EPSC, the EPSC evoked by stimulation of the perforant path appeared to be unaffected by a prior episode of status epilepticus. These results support the hypothesis that recurrent mossy fiber growth and synapse formation increases the excitatory drive to dentate granule cells and thus facilitates repetitive synchronous discharge. Activation of NMDA receptors in the recurrent pathway may contribute to seizure propagation under depolarizing conditions. Mossy fiber-granule cell synapses also are present in normal rats, where they may contribute to repetitive granule cell discharge in regions of the dentate gyrus where their numbers are significant.

scholarly journals Melatonin Modulates Dendrite Maturation and Complexity in the Dorsal- and Ventral- Dentate Gyrus Concomitantly with Its Antidepressant-Like Effect in Male Balb/C Mice

2020 ◽  
Vol 21 (5) ◽  
pp. 1724 ◽  
Author(s):  
Gerardo Bernabé Ramírez-Rodríguez ◽  
Diana Montserrat Palacios-Cabriales ◽  
Leonardo Ortiz-López ◽  
Erika Montserrat Estrada-Camarena ◽  
Nelly Maritza Vega-Rivera
Keyword(s):  
Dentate Gyrus ◽  
Main Product ◽  
Forced Swim Test ◽  
Antidepressant Drugs ◽  
Ventral Region ◽  
Internal Factors ◽  
Dendritic Trees ◽  
Swim Test ◽  
Newborn Neurons ◽  
The Impact

Adult neurogenesis occurs in the dentate gyrus (DG) of the hippocampus. New neurons help to counteract the effects of stress and several interventions including antidepressant drugs, environmental modifications and internal factors act pro-neurogenic with consequences in the dorsal and ventral DG. Melatonin, the main product synthesized by the pineal gland, induces antidepressant-like effects and modulates several events of the neurogenic process. However, the information related to the capability of melatonin to modulate dendrite maturation and complexity in the dorsal and ventral regions of the DG and their correlation with its antidepressant-like effect is absent. Thus, in this study, we analyzed the impact of melatonin (0, 0.5, 1, 2.5, 5 or 10 mg/kg) administered daily for fourteen days on the number, dendrite complexity and distribution of doublecortin (DCX)-cells in the dorsal-ventral regions of the DG in male Balb/C mice. Doublecortin is a microtubule-associated protein that is expressed during the course of dendritic maturation of newborn neurons. Also, we analyzed the impact of melatonin on despair-like behavior in the forced swim test. We first found a significant increase in the number and higher dendrite complexity, mainly with the doses of 2.5, 5 and 10 mg/kg of melatonin (81%, 122%, 78%). These cells showed more complex dendritic trees in the ventral- and the dorsal- DG. Concomitantly, the doses of 5 and 10 mg/kg of melatonin decreased depressant-like behavior (76%, 82%). Finally, the data corroborate the antidepressant-like effect of melatonin and the increasing number of doublecortin-associated cells. Besides, the data indicate that melatonin favors the number and dendrite complexity of DCX-cells in the dorsal- and ventral- region of the DG, which may explain part of the antidepressant-like effect of melatonin.

Plasticity of Both Excitatory and Inhibitory Synapses Is Associated With Seizures Induced by Removal of Chronic Blockade of Activity in Cultured Hippocampus

2006 ◽  
Vol 96 (4) ◽  
pp. 2151-2167 ◽  
Author(s):  
Suzanne B. Bausch ◽  
Shuijin He ◽  
Yelena Petrova ◽  
Xiao-Min Wang ◽  
James O. McNamara
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Field Potential ◽  
Inhibitory Synapses ◽  
Current Frequency ◽  
Synaptic Circuits ◽  
Acquired Epilepsy ◽  
The Impact ◽  
Excitatory And Inhibitory Synapses

One factor common to many neurological insults that can lead to acquired epilepsy is a loss of afferent neuronal input. Neuronal activity is one cellular mechanism implicated in transducing deafferentation into epileptogenesis. Therefore the effects of chronic activity blockade on seizure susceptibility and its underlying mechanisms were examined in organotypic hippocampal slice cultures treated chronically with the sodium channel blocker, tetrodotoxin (TTX), or the N-methyl-d-aspartate receptor (NMDAR) antagonist, d-2-amino-5-phosphonovaleric acid (d-APV). Granule cell field potential recordings in physiological buffer revealed spontaneous electrographic seizures in 83% of TTX-, 9% of d-APV-, but 0% of vehicle-treated cultures. TTX-induced seizures were not associated with membrane property alterations that would elicit granule cell hyperexcitability. Seizures were blocked by glutamate receptor antagonists, suggesting that plasticity in excitatory synaptic circuits contributed to seizures. The morphology of granule cells and their mossy fiber axons remained largely unchanged, and the number of synapses onto granule cells measured immunohistochemically was not increased in TTX- or d-APV-treated cultures. However, voltage-clamp recordings revealed that miniature excitatory postsynaptic current frequency and kinetics were increased and miniature inhibitory postsynaptic current kinetics were decreased in d-APV- and TTX-treated cultures compared with vehicle. Changes were more profound and qualitatively different in TTX- compared with d-APV-treated cultures, consistent with the dramatic effects of TTX treatment on seizure expression. We propose that chronic blockade of action potentials by TTX induces homeostatic responses including plasticity of both excitatory and inhibitory synapses. Removal of TTX unmasks the impact of these synaptic plasticities on local circuit excitability, resulting in spontaneous seizures.

scholarly journals Contributions of Mossy Fiber and CA1 Pyramidal Cell Sprouting to Dentate Granule Cell Hyperexcitability in Kainic Acid–Treated Hippocampal Slice Cultures

2004 ◽  
Vol 92 (6) ◽  
pp. 3582-3595 ◽  
Author(s):  
Suzanne B. Bausch ◽  
James O. McNamara
Keyword(s):  
Dentate Gyrus ◽  
Kainic Acid ◽  
Granule Cell ◽  
Hippocampal Slice ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Axonal Sprouting ◽  
Mossy Fiber Sprouting ◽  
Hippocampal Slice Cultures

Axonal sprouting like that of the mossy fibers is commonly associated with temporal lobe epilepsy, but its significance remains uncertain. To investigate the functional consequences of sprouting of mossy fibers and alternative pathways, kainic acid (KA) was used to induce robust mossy fiber sprouting in hippocampal slice cultures. Physiological comparisons documented many similarities in granule cell responses between KA- and vehicle-treated cultures, including: seizures, epileptiform bursts, and spontaneous excitatoty postsynaptic currents (sEPSCs) >600pA. GABAergic control and contribution of glutamatergic synaptic transmission were similar. Analyses of neurobiotin-filled CA1 pyramidal cells revealed robust axonal sprouting in both vehicle- and KA-treated cultures, which was significantly greater in KA-treated cultures. Hilar stimulation evoked an antidromic population spike followed by variable numbers of postsynaptic potentials (PSPs) and population spikes in both vehicle- and KA-treated cultures. Despite robust mossy fiber sprouting, knife cuts separating CA1 from dentate gyrus virtually abolished EPSPs evoked by hilar stimulation in KA-treated but not vehicle-treated cultures, suggesting a pivotal role of functional afferents from CA1 to dentate gyrus in KA-treated cultures. Together, these findings demonstrate striking hyperexcitability of dentate granule cells in long-term hippocampal slice cultures after treatment with either vehicle or KA. The contribution to hilar-evoked hyperexcitability of granule cells by the unexpected axonal projection from CA1 to dentate in KA-treated cultures reinforces the idea that axonal sprouting may contribute to pathologic hyperexcitability of granule cells.

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