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

Spigelman, Igor; Yan, Xiao‐Xin; Obenaus, André; Lee, E.Y.-S; Wasterlain, Claude G.; Ribak, Charles E.

doi:10.1016/s0306-4522(98)00028-1

Cited by 160 publications

(133 citation statements)

References 52 publications

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“…We then show that this robustness can be overcome by the inclusion of a small percentage of highly interconnected GCs serving as network ''hubs,'' even while maintaining a constant number of connections throughout the network. Importantly, our in silico implementation of hubs closely resembles the presence of GCs with hilar basal dendrites in the biological circuit (23). This correspondence, combined with the prediction of our model that effective hubs will have both enhanced incoming and outgoing connectivity, provides a mechanism for the contribution of GCs with hilar basal dendrites in promoting hyperexcitability after brain injury.…”

supporting

confidence: 54%

“…This dendrite does not extend into the molecular layer but rather toward the hilus, and it synapses with mossy fibers, thereby creating excitatory circuits similar to those formed by apical dendrites (35). The percentage of GCs that have these hilar basal dendrites is relatively small, with estimates ranging from 5 to 20% of GCs (23,(35)(36)(37). Interestingly, this estimate is sufficiently large, even at its minimum, to provide enough hubs to promote hyperexcitability according to the predictions of our model.…”

Section: Discussionmentioning

confidence: 76%

“…After injury, however, a subset of GCs can be found that not only have apical dendrites but a long basal dendrite as well (23). This dendrite does not extend into the molecular layer but rather toward the hilus, and it synapses with mossy fibers, thereby creating excitatory circuits similar to those formed by apical dendrites (35).…”

Section: Discussionmentioning

confidence: 99%

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Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures

Morgan

Soltész

2008

Proc. Natl. Acad. Sci. U.S.A.

319

278

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Many complex neuronal circuits have been shown to display nonrandom features in their connectivity. However, the functional impact of nonrandom network topologies in neurological diseases is not well understood. The dentate gyrus is an excellent circuit in which to study such functional implications because proepileptic insults cause its structure to undergo a number of specific changes in both humans and animals, including the formation of previously nonexistent granule cell-to-granule cell recurrent excitatory connections. Here, we use a large-scale, biophysically realistic model of the epileptic rat dentate gyrus to reconnect the aberrant recurrent granule cell network in four biologically plausible ways to determine how nonrandom connectivity promotes hyperexcitability after injury. We find that network activity of the dentate gyrus is quite robust in the face of many major alterations in granule cell-to-granule cell connectivity. However, the incorporation of a small number of highly interconnected granule cell hubs greatly increases network activity, resulting in a hyperexcitable, potentially seizure-prone circuit. Our findings demonstrate the functional relevance of nonrandom microcircuits in epileptic brain networks, and they provide a mechanism that could explain the role of granule cells with hilar basal dendrites in contributing to hyperexcitability in the pathological dentate gyrus.basal dendrite ͉ computational model ͉ epilepsy ͉ granule cell ͉ scale-free N umerous studies have indicated that connectivity in a wide variety of neural systems exhibits highly nonrandom characteristics. For example, in the nervous system of the Caenorhabditis elegans worm, of which the complete structure has been described (1), it was shown that a number of local connectivity patterns (network motifs) are over-or underrepresented compared with what would be present in a random network (2-4). Furthermore, computational analysis has indicated that the dynamic properties of these network motifs could contribute to their relative abundance, closely tying functional properties to the structural network (5). Nonrandom connectivity features have been discovered in mammalian cortices as well (6-10). Such networks exhibit high degrees of local clustering with short path lengths [small-world topology (11-13)], power law distributions of connectivity [scale-free topology (11,13,14)], and nonrandom distributions of connection strengths (8). Additionally, it has been shown that connection probabilities demonstrate fine-scale specificity that depends both on neuronal type and the presence or absence of other connections in the network (15, 16).Although nonrandom structural features of neuronal networks have been of great interest recently, and the role of some of these features in network dynamics and information processing has been investigated (5,(17)(18)(19), the contribution of nonrandom microcircuit connectivity to the functional properties of large, complex brain regions, particularly in epilepsy, remains poorly understood. The...

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supporting

confidence: 54%

Section: Discussionmentioning

confidence: 76%

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Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures

Morgan

Soltész

2008

Proc. Natl. Acad. Sci. U.S.A.

319

278

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“…2 A for a description of predicted GFP-expressing granule cell age). Previous studies, using Golgi and biocytin labeling techniques, revealed numerous granule cells with hilar basal dendrites in epileptic animals but not in control animals (Spigelman et al, 1998;Buckmaster and Dudek, 1999;Yan et al, 2001). Analysis of 4-to 16-week-old GFP-expressing granule cells in normal and epileptic animals confirmed the results of these previous studies.…”

Section: Gfp-expressing Granule Cells From Epileptic Animals Frequentmentioning

confidence: 89%

“…Mature granule cells normally lack basal dendrites. In epileptic animals, however, granule cells with basal dendrites are common (Spigelman et al, 1998;Buckmaster and Dudek, 1999;Yan et al, 2001). Basal dendrites are significant because they project into the dentate hilus and are innervated by granule cell axons in this region, creating recurrent excitatory circuits (Ribak et al, 2000;Austin and Buckmaster, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pilocarpine-Induced Seizures Cause Selective Time-Dependent Changes to Adult-Generated Hippocampal Dentate Granule Cells

Walter¹,

Murphy²,

Pun³

et al. 2007

J. Neurosci.

163

176

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Aberrantly interconnected granule cells are characteristic of temporal lobe epilepsy. By reducing network stability, these abnormal neurons may contribute directly to disease development. Only subsets of granule cells, however, exhibit abnormalities. Why this is the case is not known. Ongoing neurogenesis in the adult hippocampus may provide an explanation. Newly generated granule cells may be uniquely vulnerable to environmental disruptions relative to their mature neighbors. Here, we determine whether there is a critical period after neuronal birth during which neuronal integration can be disrupted by an epileptogenic insult. By bromodeoxyuridine birthdating cells in green fluorescent protein-expressing transgenic mice, we were able to noninvasively label granule cells born 8 weeks before (mature), 1 week before (immature), or 3 weeks after (newborn) pilocarpineepileptogenesis. Neuronal morphology was examined 4 and 8 weeks after pilocarpine treatment. Strikingly, almost 50% of immature granule cells exposed to pilocarpine-epileptogenesis exhibited aberrant hilar basal dendrites. In contrast, only 9% of mature granule cells exposed to the identical insult possessed basal dendrites. Moreover, newborn cells were even more severely impacted than immature cells, with 40% exhibiting basal dendrites and an additional 20% exhibiting migration defects. In comparison, Ͻ5% of neurons from normal animals exhibited either abnormality, regardless of age. Together, these data demonstrate the existence of a critical period after the birth of adult-generated neurons during which they are vulnerable to being recruited into epileptogenic neuronal circuits. Pathological brain states therefore may pose a significant hurdle for the appropriate integration of newly born endogenous, and exogenous, neurons.

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Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry

et al. 2000

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Mossy fiber sprouting into the inner molecular layer of the dentate gyrus is an important neuroplastic change found in animal models of temporal lobe epilepsy and in humans with this type of epilepsy. Recently, we reported in the perforant path stimulation model another neuroplastic change for dentate granule cells following seizures: hilar basal dendrites (HBDs). The present study determined whether status epilepticus-induced HBDs on dentate granule cells occur in the pilocarpine model of temporal lobe epilepsy and whether these dendrites are targeted by mossy fibers. Retrograde transport of biocytin following its ejection into stratum lucidum of CA3 was used to label granule cells for both light and electron microscopy. Granule cells with a heterogeneous morphology, including recurrent basal dendrites, and locations outside the granule cell layer were observed in control preparations. Preparations from both pilocarpine and kainate models of temporal lobe epilepsy also showed granule cells with HBDs. These dendrites branched and extended into the hilus of the dentate gyrus and were shown to be present on 5% of the granule cells in pilocarpine-treated rats with status epilepticus, whereas control rats had virtually none. Electron microscopy was used to determine whether HBDs were postsynaptic to axon terminals in the hilus, a site where mossy fiber collaterals are prevalent. Labeled granule cell axon terminals were found to form asymmetric synapses with labeled HBDs. Also, unlabeled, large mossy fiber boutons were presynaptic to HBDs of granule cells. These results indicate that HBDs are present in the pilocarpine model of temporal lobe epilepsy, confirm the presence of HBDs in the kainate model, and show that HBDs are postsynaptic to mossy fibers. These new mossy fiber synapses with HBDs may contribute to additional recurrent excitatory circuitry for granule cells.

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

Cited by 160 publications

References 52 publications

Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures

Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures

Pilocarpine-Induced Seizures Cause Selective Time-Dependent Changes to Adult-Generated Hippocampal Dentate Granule Cells

Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry

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