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Ivan Soltesz - One of the best experts on this subject based on the ideXlab platform.
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role of Mossy fiber sprouting and Mossy Cell loss in hyperexcitability a network model of the dentate gyrus incorporating Cell types and axonal topography
Journal of Neurophysiology, 2005Co-Authors: Vijayalakshmi Santhakumar, Ildiko Aradi, Ivan SolteszAbstract: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 und...
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Role of Mossy fiber sprouting and Mossy Cell loss in hyperexcitability: a network model of the dentate gyrus incorporating Cell types and axonal topography. J Neurophysiol 93:437–453
2005Co-Authors: Vijayalakshmi Santhakumar, Ildiko Aradi, Ivan SolteszAbstract:Role of Mossy fiber sprouting and Mossy Cell loss in hyperexcitability: a network model of the dentate gyrus incorporating Cell types and axonal topography. J Neurophysiol 93: 437–453, 2005. First pub-lished September 1, 2004; doi:10.1152/jn.00777.2004. Mossy Cell loss and Mossy fiber sprouting are two characteristic consequences of repeated seizures and head trauma. However, their precise contribu-tions 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 compu-tational 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 ex-perimental 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
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granule Cell hyperexcitability in the early post traumatic rat dentate gyrus the irritable Mossy Cell hypothesis
The Journal of Physiology, 2000Co-Authors: Vijayalakshmi Santhakumar, Roland A. Bender, Michael Frotscher, Stephen T Ross, Greg S Hollrigel, Zsolt Toth, Ivan SolteszAbstract:1. Cytochemical and in vitro whole-Cell patch clamp techniques were used to investigate granule Cell hyperexcitability in the dentate gyrus 1 week after fluid percussion head trauma. 2. The percentage decrease in the number of hilar interneurones labelled with either GAD67 or parvalbumin mRNA probes following trauma was not different from the decrease in the total population of hilar Cells, indicating no preferential survival of interneurones with respect to the non-GABAergic hilar Cells, i.e. the Mossy Cells. 3. Dentate granule Cells following trauma showed enhanced action potential discharges, and longer-lasting depolarizations, in response to perforant path stimulation, in the presence of the GABAA receptor antagonist bicuculline. 4. There was no post-traumatic alteration in the perforant path-evoked monosynaptic excitatory postsynaptic currents (EPSCs), or in the intrinsic properties of granule Cells. However, after trauma, the monosynaptic EPSC was followed by late, polysynaptic EPSCs, which were not present in controls. 5. The late EPSCs in granule Cells from fluid percussion-injured rats were not blocked by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV), but were eliminated by both the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the AMPA receptor antagonist GYKI 53655. 6. In addition, the late EPSCs were not present in low (0.5 mM) extraCellular calcium, and they were also eliminated by the removal of the dentate hilus from the slice. 7. Mossy hilar Cells in the traumatic dentate gyrus responded with significantly enhanced, prolonged trains of action potential discharges to perforant path stimulation. 8. These data indicate that surviving Mossy Cells play a crucial role in the hyperexcitable responses of the post-traumatic dentate gyrus.
Kazu Nakazawa - One of the best experts on this subject based on the ideXlab platform.
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dentate Mossy Cell and pattern separation
Neuron, 2017Co-Authors: Kazu NakazawaAbstract:Three studies by Danielson et al. (2017), GoodSmith et al. (2017), and Sensai and Buzsaki (2017) distinguish in vivo firing properties of dentate Mossy Cells from granule Cells during behavior. Robust spatial remapping of Mossy Cells, in contrast to sparse firing of granule Cells, suggests differential involvement in pattern separation.
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Hilar Mossy Cell circuitry controlling dentate granule Cell excitability
Frontiers in neural circuits, 2013Co-Authors: Seiichiro Jinde, Veronika Zsiros, Kazu NakazawaAbstract:Glutamatergic hilar Mossy Cells of the dentate gyrus can either excite or inhibit distant granule Cells, depending on whether their direct excitatory projections to granule Cells or their projections to local inhibitory interneurons dominate. However, it remains controversial whether the net effect of Mossy Cell loss is granule Cell excitation or inhibition. Clarifying this controversy has particular relevance to temporal lobe epilepsy, which is marked by dentate granule Cell hyperexcitability and extensive loss of dentate hilar Mossy Cells. Two diametrically opposed hypotheses have been advanced to explain this granule Cell hyperexcitability – the “dormant basket Cell” and the “irritable Mossy Cell” hypotheses. The “dormant basket Cell” hypothesis proposes that Mossy Cells normally exert a net inhibitory effect on granule Cells and therefore their loss causes dentate granule Cell hyperexcitability. The “irritable Mossy Cell” hypothesis takes the opposite view that Mossy Cells normally excite granule Cells and that the surviving Mossy Cells in epilepsy increase their activity, causing granule Cell excitation. The inability to eliminate Mossy Cells selectively has made it difficult to test these two opposing hypotheses. To this end, we developed a transgenic toxin-mediated, Mossy Cell-ablation mouse line. Using these mutants, we demonstrated that the extensive elimination of hilar Mossy Cells causes granule Cell hyperexcitability, although the Mossy Cell loss observed appeared insufficient to cause clinical epilepsy. In this review, we focus on this topic and also suggest that different interneuron populations may mediate Mossy Cell-induced translamellar lateral inhibition and intralamellar recurrent inhibition. These unique local circuits in the dentate hilar region may be centrally involved in the functional organization of the dentate gyrus.
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hilar Mossy Cell degeneration causes transient dentate granule Cell hyperexcitability and impaired pattern separation
Neuron, 2012Co-Authors: Seiichiro Jinde, Veronika Zsiros, Zhihong Jiang, Kazuhito Nakao, James Pickel, Kenji Kohno, Juan E Belforte, Kazu NakazawaAbstract:Summary Although excitatory Mossy Cells of the hippocampal hilar region are known to project both to dentate granule Cells and to interneurons, it is as yet unclear whether Mossy Cell activity's net effect on granule Cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/ loxP system, in which diphtheria toxin receptor was selectively expressed in Mossy Cells. One week after injecting toxin into this line, Mossy Cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or Mossy-fiber sprouting 5–6 weeks after Mossy Cell degeneration. These results indicate that the net effect of Mossy Cell excitation is to inhibit granule Cell activity and enable dentate pattern separation.
Vijayalakshmi Santhakumar - One of the best experts on this subject based on the ideXlab platform.
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modeling circuit alterations in epilepsy a focus on Mossy Cell loss and Mossy fiber sprouting in the dentate gyrus
Computational Neuroscience in Epilepsy, 2008Co-Authors: Vijayalakshmi SanthakumarAbstract:Publisher Summary This chapter provides an overview of the general approach and considerations for developing a large-scale model to study epileptogenesis with the focus on simulating the effects of Mossy fiber sprouting and hilar Cell loss in the dentate circuits. It presents the results of simulation studies to highlight the applicability of the technique and insights obtained based on such large-scale modeling approaches. Understanding a complex network phenomenon like epilepsy requires a conceptual framework that links the biophysical properties of individual neurons and the circuit where the disease manifests. Computational modeling provides a means to bridge these levels and is ideally suited to study dynamical diseases such as epilepsy. There is increasing physiological evidence for a role for Mossy Cells in spreading hyperexcitability through their long-range connections. Implementation of large-scale models of the dentate gyrus allows for examining the net effect of these distinctive network alterations on the function of the dentate “gate” independent of changes intrinsic, extraCellular or ephaptic properties. The novel insights into the development and progression of epilepsy revealed by simulation studies offer a compelling case for the use of data-driven simulations in understanding complex network diseases such as epilepsy. It is anticipated that network modeling methods will make it possible to test the circuit effects of specific therapeutic manipulations and allow for uniquely tailoring treatment to the distinct underlying cause of a seizure disorder.
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role of Mossy fiber sprouting and Mossy Cell loss in hyperexcitability a network model of the dentate gyrus incorporating Cell types and axonal topography
Journal of Neurophysiology, 2005Co-Authors: Vijayalakshmi Santhakumar, Ildiko Aradi, Ivan SolteszAbstract: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 und...
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Role of Mossy fiber sprouting and Mossy Cell loss in hyperexcitability: a network model of the dentate gyrus incorporating Cell types and axonal topography. J Neurophysiol 93:437–453
2005Co-Authors: Vijayalakshmi Santhakumar, Ildiko Aradi, Ivan SolteszAbstract:Role of Mossy fiber sprouting and Mossy Cell loss in hyperexcitability: a network model of the dentate gyrus incorporating Cell types and axonal topography. J Neurophysiol 93: 437–453, 2005. First pub-lished September 1, 2004; doi:10.1152/jn.00777.2004. Mossy Cell loss and Mossy fiber sprouting are two characteristic consequences of repeated seizures and head trauma. However, their precise contribu-tions 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 compu-tational 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 ex-perimental 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
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granule Cell hyperexcitability in the early post traumatic rat dentate gyrus the irritable Mossy Cell hypothesis
The Journal of Physiology, 2000Co-Authors: Vijayalakshmi Santhakumar, Roland A. Bender, Michael Frotscher, Stephen T Ross, Greg S Hollrigel, Zsolt Toth, Ivan SolteszAbstract:1. Cytochemical and in vitro whole-Cell patch clamp techniques were used to investigate granule Cell hyperexcitability in the dentate gyrus 1 week after fluid percussion head trauma. 2. The percentage decrease in the number of hilar interneurones labelled with either GAD67 or parvalbumin mRNA probes following trauma was not different from the decrease in the total population of hilar Cells, indicating no preferential survival of interneurones with respect to the non-GABAergic hilar Cells, i.e. the Mossy Cells. 3. Dentate granule Cells following trauma showed enhanced action potential discharges, and longer-lasting depolarizations, in response to perforant path stimulation, in the presence of the GABAA receptor antagonist bicuculline. 4. There was no post-traumatic alteration in the perforant path-evoked monosynaptic excitatory postsynaptic currents (EPSCs), or in the intrinsic properties of granule Cells. However, after trauma, the monosynaptic EPSC was followed by late, polysynaptic EPSCs, which were not present in controls. 5. The late EPSCs in granule Cells from fluid percussion-injured rats were not blocked by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV), but were eliminated by both the non-NMDA glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the AMPA receptor antagonist GYKI 53655. 6. In addition, the late EPSCs were not present in low (0.5 mM) extraCellular calcium, and they were also eliminated by the removal of the dentate hilus from the slice. 7. Mossy hilar Cells in the traumatic dentate gyrus responded with significantly enhanced, prolonged trains of action potential discharges to perforant path stimulation. 8. These data indicate that surviving Mossy Cells play a crucial role in the hyperexcitable responses of the post-traumatic dentate gyrus.
Paul S. Buckmaster - One of the best experts on this subject based on the ideXlab platform.
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surviving Mossy Cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy
Hippocampus, 2015Co-Authors: Wei Zhang, Ajoy K Thamattoor, Christopher Leroy, Paul S. BuckmasterAbstract:Numerous hypotheses of temporal lobe epileptogenesis have been proposed, and several involve hippocampal Mossy Cells. Building on previous hypotheses we sought to test the possibility that after epileptogenic injuries surviving Mossy Cells develop into super-connected seizure-generating hub Cells. If so, they might require more Cellular machinery and consequently have larger somata, elongate their dendrites to receive more synaptic input, and display higher frequencies of miniature excitatory synaptic currents (mEPSCs). To test these possibilities pilocarpine-treated mice were evaluated using GluR2-immunocytochemistry, whole-Cell recording, and biocytin-labeling. Epileptic pilocarpine-treated mice displayed substantial loss of GluR2-positive hilar neurons. Somata of surviving neurons were 1.4-times larger than in controls. Biocytin-labeled Mossy Cells also were larger in epileptic mice, but dendritic length per Cell was not significantly different. The average frequency of mEPSCs of Mossy Cells recorded in the presence of tetrodotoxin and bicuculline was 3.2-times higher in epileptic pilocarpine-treated mice compared to controls. Other parameters of mEPSCs were similar in both groups. Average input resistance of Mossy Cells in epileptic mice was reduced to 63% of controls, which is consistent with larger somata and would tend to make surviving Mossy Cells less excitable. Other intrinsic physiological characteristics examined were similar in both groups. Increased excitatory synaptic input is consistent with the hypothesis that surviving Mossy Cells develop into aberrantly super-connected seizure-generating hub Cells, and soma hypertrophy is indirectly consistent with the possibility of axon sprouting. However, no obvious evidence of hyperexcitable intrinsic physiology was found. Furthermore, similar hypertrophy and hyper-connectivity has been reported for other neuron types in the dentate gyrus, suggesting Mossy Cells are not unique in this regard. Thus, findings of the present study reveal epilepsy-related changes in Mossy Cell anatomy and synaptic input but do not strongly support the hypothesis that Mossy Cells develop into seizure-generating hub Cells.
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Mossy Cell dendritic structure quantified and compared with other hippocampal neurons labeled in rats in vivo
Epilepsia, 2012Co-Authors: Paul S. BuckmasterAbstract:Mossy Cells are likely to contribute to normal hippocampal function and to the pathogenesis of neurologic disorders that involve the hippocampus, including epilepsy. Mossy Cells are the least well-characterized excitatory neurons in the hippocampus. Their somatic and dendritic morphology has been described qualitatively but not quantitatively. In the present study rat Mossy Cells were labeled intraCellularly with biocytin in vivo. Somatic and dendritic structure was reconstructed three-dimensionally. For comparison, granule Cells, CA3 pyramidal Cells, and CA1 pyramidal Cells were labeled and analyzed using the same approach. Among the four types of hippocampal neurons, granule Cells had the smallest somata, fewest primary dendrites and dendritic branches, and shortest total dendritic length. CA1 pyramidal Cells had the most dendritic branches and longest total dendritic length. Mossy Cells and CA3 pyramidal Cells both had large somata and similar total dendritic lengths. However, Mossy Cell dendrites branched less than CA3 pyramidal Cells, especially close to the soma. These findings suggest that Mossy Cells have dendritic features that are not identical to any other type of hippocampal neuron. Therefore, electrotonic properties that depend on soma-dendritic structure are likely to be distinct in Mossy Cells compared to other neurons.
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ultrastructural localization of neurotransmitter immunoreactivity in Mossy Cell axons and their synaptic targets in the rat dentate gyrus
Hippocampus, 1997Co-Authors: Jurgen H Wenzel, Paul S. Buckmaster, N L Anderson, Mareike E Wenzel, Philip A SchwartzkroinAbstract:Electrophysiologically identified and intraCellularly biocytin-labeled Mossy Cells in the dentate hilus of the rat were studied using electron microscopy and postembedding immunogold techniques. Ultrathin sections containing a labeled Mossy Cell or its axon collaterals were reacted with antisera against the excitatory neurotransmitter glutamate and against the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). From single- and double-immunolabeled preparations, we found that 1) Mossy Cell axon terminals made asymmetric contacts onto postsynaptic targets in the hilus and stratum moleculare of the dentate gyrus and showed immunoreactivity primarily for glutamate, but never for GABA; 2) in the hilus, glutamate-positive Mossy Cell axon terminals targeted GABA-positive dendritic shafts of hilar interneurons and GABA-negative dendritic spines; and 3) in the inner molecular layer, the Mossy Cell axon formed asymmetric synapses with dendritic spines associated with GABA-negative (presumably granule Cell) dendrites. The results of this study support the view that excitatory (glutamatergic) Mossy Cell terminals contact GABAergic interneurons and non-GABAergic neurons in the hilar region and GABA-negative granule Cells in the stratum moleculare. This pattern of connectivity is consistent with the hypothesis that Mossy Cells provide excitatory feedback to granule Cells in a dentate gyrus associational network and also activate local hilar inhibitory elements.
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Mossy Cell axonal projections to the dentate gyrus molecular layer in the rat hippocampal slice
Hippocampus, 1992Co-Authors: Paul S. Buckmaster, Ben W Strowbridge, Dennis D Kunkel, Donna L Schmiege, Philip A SchwartzkroinAbstract:The ipsilateral associational pathway connects different septotemporal levels of the dentate gyrus. Neurons of the dentate hilus project hundreds of micrometers from the Cells of origin to the inner molecular layer. The authors hypothesized that Mossy Cells, the major Cell type of the hilus, also project locally to the inner molecular layer. Within a 400 microns slice, Mossy Cells were (1) recorded intraCellularly while the inner molecular layer was stimulated to test for antidromic responses, and (2) labeled with biocytin and examined with light and electron microscopy for axonal projections into the molecular layer. The authors found that Mossy Cells can be antidromically activated by inner molecular layer stimulation and that axonal projections to the molecular layer can be visualized within a 400 microns hippocampal slice. In 13 of 19 intraCellularly labeled and electrophysiologically characterized Mossy Cells, collaterals could be traced into the molecular layer. These results suggest that Mossy Cells contribute to the ipsilateral associational pathway and also participate in local recurrent circuitry to influence granule Cell activity.
Seiichiro Jinde - One of the best experts on this subject based on the ideXlab platform.
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Hilar Mossy Cell circuitry controlling dentate granule Cell excitability
Frontiers in neural circuits, 2013Co-Authors: Seiichiro Jinde, Veronika Zsiros, Kazu NakazawaAbstract:Glutamatergic hilar Mossy Cells of the dentate gyrus can either excite or inhibit distant granule Cells, depending on whether their direct excitatory projections to granule Cells or their projections to local inhibitory interneurons dominate. However, it remains controversial whether the net effect of Mossy Cell loss is granule Cell excitation or inhibition. Clarifying this controversy has particular relevance to temporal lobe epilepsy, which is marked by dentate granule Cell hyperexcitability and extensive loss of dentate hilar Mossy Cells. Two diametrically opposed hypotheses have been advanced to explain this granule Cell hyperexcitability – the “dormant basket Cell” and the “irritable Mossy Cell” hypotheses. The “dormant basket Cell” hypothesis proposes that Mossy Cells normally exert a net inhibitory effect on granule Cells and therefore their loss causes dentate granule Cell hyperexcitability. The “irritable Mossy Cell” hypothesis takes the opposite view that Mossy Cells normally excite granule Cells and that the surviving Mossy Cells in epilepsy increase their activity, causing granule Cell excitation. The inability to eliminate Mossy Cells selectively has made it difficult to test these two opposing hypotheses. To this end, we developed a transgenic toxin-mediated, Mossy Cell-ablation mouse line. Using these mutants, we demonstrated that the extensive elimination of hilar Mossy Cells causes granule Cell hyperexcitability, although the Mossy Cell loss observed appeared insufficient to cause clinical epilepsy. In this review, we focus on this topic and also suggest that different interneuron populations may mediate Mossy Cell-induced translamellar lateral inhibition and intralamellar recurrent inhibition. These unique local circuits in the dentate hilar region may be centrally involved in the functional organization of the dentate gyrus.
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hilar Mossy Cell degeneration causes transient dentate granule Cell hyperexcitability and impaired pattern separation
Neuron, 2012Co-Authors: Seiichiro Jinde, Veronika Zsiros, Zhihong Jiang, Kazuhito Nakao, James Pickel, Kenji Kohno, Juan E Belforte, Kazu NakazawaAbstract:Summary Although excitatory Mossy Cells of the hippocampal hilar region are known to project both to dentate granule Cells and to interneurons, it is as yet unclear whether Mossy Cell activity's net effect on granule Cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/ loxP system, in which diphtheria toxin receptor was selectively expressed in Mossy Cells. One week after injecting toxin into this line, Mossy Cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or Mossy-fiber sprouting 5–6 weeks after Mossy Cell degeneration. These results indicate that the net effect of Mossy Cell excitation is to inhibit granule Cell activity and enable dentate pattern separation.