epilepsy-associated reelin dysfunction induces granule...

Epilepsy-Associated Reelin Dysfunction Induces Granule Cell Dispersion in theDentate Gyrusq

M Frotscher, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyCA Haas, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

� 2017 Elsevier Inc. All rights reserved.

Introduction 1BackgrounddGranule Cell Dispersion in Epilepsyda Migration Defect? 1Methods 2Recent Results 3Unilateral Injection of Kainate, an Agonist of the Excitatory Transmitter Glutamate, Results in the Development of GCD in Mice 3Reelin’s Role in the Development of GCD 4Reelin Keeps Adult Granule Cells in Register 5

Summary and Conclusions 5Future Directions 5Further Reading 7

Introduction

Ammon’s horn sclerosis (AHS) is a hallmark of temporal lobe epilepsy. AHS is characterized by neuronal loss in hippocampalregions CA3 and CA1 and in the hilus of the dentate gyrus, and by granule cell dispersion (GCD). The term sclerosis describes a glialhypertrophy accompanying the neuronal loss. The neuron loss is likely to represent excitotoxic cell death associated with increasedcalcium entry into the cells. This mechanism of cell death is supported by studies showing that intracellular application of calciumbuffers prevents excitotoxic cell death of hilar neurons. Neurons in hippocampal region CA2, which is located in between CA1 andCA3, are less vulnerable and are particularly rich in calcium-binding proteins.

The factors that induce a broadening of the granule cell layerdie, granule cell dispersiondare less clear. Does increased neuronalactivity force the granule cells to leave their normally tightly packed layer? Does seizure activity stimulate neurogenesis in the den-tate gyrus, leading to an increase in neuron number and thus to a broadening of the granule cell layer? Does glial hypertrophy inAHS play a role in the development of granule cell dispersion?

In this article, we summarize our recent studies which addressed these questions. In these studies, we used tissue samples fromtemporal lobe epilepsy (TLE) patients subjected to hippocampal resection for therapeutical reasons. In addition, we used tissuefrom mice that had received a unilateral hippocampal injection of kainate. By comparing our results in human tissue and in exper-imental animals, we obtained new insights into the processes leading to the development of granule cell dispersion in epilepsy.

BackgrounddGranule Cell Dispersion in Epilepsyda Migration Defect?

Granule cell dispersion is best described as an abnormal broadening of the granule cell layer, with many granule cells migrating farinto themolecular layer (Fig. 1). GCD is regularly associated with Ammon’s horn sclerosis, but there are also cases of Ammon’s hornsclerosis lacking a prominent GCD. There is strong evidence that Ammon’s horn sclerosis, the degeneration of neurons in hippo-campal regions CA1 and CA3 and in the hilus of the dentate gyrus, represents excitotoxic changes resulting from increased neuronalactivity. Does this also hold true for GCD? The neurons that migrate out into the molecular layer do not show signs of neuronaldegeneration. Alternatively, is GCD a migration defect of the granule cells during development that eventually leads to epilepsy?It would not be too far-fetched to assume a developmental migration defect, as there are mouse mutants that show a structuralphenotype reminiscent of GCD and a functional phenotype of seizures/epilepsy.

A more scattered distribution of the granule cells leads to an overlap of the normally segregated input and output sides of thegranule cells. In a densely packed granule cell layer, the input side (ie, the granule cell dendritic arbors in the molecular layer) isnormally separated from the output side (the mossy fiber axons invading the hilus). A loss of this clear-cut lamination willallow more superficially located granule cells to contact dendrites of deeply located neurons, resulting in an increased granulecell-to-granule cell connectivity. Would this aberrant circuitry contribute to increased excitability of the granule cells, resulting inepileptic activity?

qChange history: December 2015. Author Carola Haas and author Michael Frotscher made minor corrections to the text with a major change to the paragraph

“Future directions” (the changes are on page 12). In addition, a few references were added. They were not cited in the text since all other references of the

original manuscript were also not cited in the text but added as “Further Reading”.

Reference Module in Neuroscience and Biobehavioral Psychology http://dx.doi.org/10.1016/B978-0-12-809324-5.00032-8 1

http://dx.doi.org/10.1016/B978-0-12-809324-5.00032-8

One mutant that shows a migration defect similar to GCD is the reeler mouse lacking the extracellular matrix protein reelin.Reelin is known to be synthesized and secreted by Cajal-Retzius cells in the marginal zones of cortex and hippocampus, and thereare severe migration defects in these regions in the reeler mutant. Could it be that GCD in epileptic patients is associated with analtered reelin expression?

As a first step towards a better understanding of GCD, we looked at reelin expression in tissue samples from epileptic patientswith GCD and in samples from autopsy controls. These control patients did not suffer from epileptic seizures and did not showAmmon’s horn sclerosis and GCD. We measured reelin expression by real-time PCR and quantified reelin-expressing cells usingin situ hybridization for reelin mRNA. We found a significant decrease in reelin expression in patients with granule cell dispersionwith both methods. Moreover, there was an inverse correlation between the number of reelin mRNA-expressing cells in the dentategyrus and the extent of granule cell dispersion, quantified by measuring the width of the granule cell layer. While these findingspointed to a role of reelin in the development of granule cell dispersion, they could not clarify whether decreased reelinexpression during development had caused granule cell dispersion which in turn led to epilepsy or, alternatively, epilepticseizures interfered with reelin expression, leading to GCD. For obvious reasons, these questions could not be addressed instudies of tissue samples from patients.

Methods

We used tissue samples from TLE patients and a mouse epilepsy model that recapitulates the main histopathological and electro-physiological features of human TLE. A single unilateral injection of the glutamate agonist kainate (KA) into the hippocampus ofadult mice induced spontaneous, focal epileptic seizures and Ammon’s horn sclerosis, including GCD. We used cresyl violet stain-ing, immunohistochemistry, in situ hybridization and real-time PCR analysis to monitor cell death, GCD development, neurogen-esis, glial cell proliferation, and reelin expression in human tissue and tissue obtained from kainate-injected mice.

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Figure 1 Morphology of normal and epileptic human hippocampus stained with cresyl violet. (A) Human control hippocampus with normal distri-bution of neurons in hippocampal subfields and in the dentate gyrus, where the granule cells are located in a dense layer. (B) Epileptic human hippo-campus with characteristic features of Ammon’s horn sclerosis. Selective cell loss is obvious in hippocampal subfields CA1 and CA3. The granule celllayer is dispersed. (C) Granule cell layer of a normal human dentate gyrus. The granule cells are arranged in a densely packed layer. (D) Loss ofdense granule cell packing (granule cell dispersion) in temporal lobe epilepsy. Scale bars A, B: 600 mm; C, D: 75 mm. CA1, CA2, CA3, hippocampalsubfields; GCL, granule cell layer. Reproduced from Haas, A., Frotscher, M., 2004. Migration disorders and epilepsy. In: Herdegen, T., Delgado-García, J.M. (Eds.), Brain. Damage and Repair. Kluwer Academic Publishers, Dordrecht, pp. 391–402; copyright Kluwer Academic Publishers.

2 Epilepsy-Associated Reelin Dysfunction Induces Granule Cell Dispersion in the Dentate Gyrus

Recent Results

Unilateral Injection of Kainate, an Agonist of the Excitatory Transmitter Glutamate, Results in the Development of GCD in Mice

Increased neuronal activity is associated with an increased release of the excitatory neurotransmitter, glutamate. Thus, glutamatereceptor agonists, such as kainate, are often injected into animals to induce epileptic activity. Unilateral injection of kainate intoone hippocampus (in mice) was not only found to induce seizure activity but also to lead to Ammon’s horn sclerosis with neuronaldegeneration in CA1 and CA3 and granule cell dispersion in the dentate gyrus. Interestingly, these degenerative changes are notfound on the contralateral, non-injected side.

After a latency period of 2 weeks, the animals developed seizure activity as monitored by EEG recordings. They also developeda prominent granule cell dispersion on the side of kainate injection but not on the contralateral side, indicating that GCD resultedfrom the injection of the excitotoxin. The broadening of the granule cell layer developed progressively; GCD was evident as early as1 week post injection and was fully expressed after 6 weeks (Fig. 2).

What is the nature of kainate-induced GCD? Is it a migration of fully differentiated granule cells, or does seizure activity increaseneurogenesis and aberrant migration of the newly generated granule cells? It is generally accepted that post-migratory neuroblaststhat are about to differentiate their dendritic and axonal arbors are no longer able to migrate. How, then, could fully differentiatedgranule cells migrate out of a densely packed granule cell layer?

In our experimental animals, we were in the position to address these questions by injecting them with bromodeoxyuridine(BrdU), a marker of newly generated cells. We found that neurogenesis was significantly decreased on the side of kainate injection(where GCD occurs) when compared to the non-injected control side (where no GCD was observed). Given the paucity of neuro-genesis on the side that shows GCD, we concluded that adult, differentiated granule cells have “migrated”, and that GCD does notrepresent an abnormal migration of newly generated granule cells. The cessation of neurogenesis on the side of kainate injectioncame as a surprise, since studies of other epilepsy models had shown epileptic activity to induce neurogenesis. Further, while neuro-genesis had ceased on the side of kainate injection, we noticed an increased gliogenesis, as revealed by double labeling for the astro-cytic marker GFAP (glial fibrillary acidic protein) and BrdU. It is reasonable to assume that this increased formation of astrocytes,particularly in the hilar region and in CA1 and CA3, is associated with the excitotoxic neurodegenerative changes observed in theseregions. There was also an increase in activated microglial cells, as demonstrated by labeling for the microglial marker Iba1.

Next, an attempt was made to determine whether or not increased neurogenesis is involved in the formation of GCD in humanepileptic patients. To this end we used immunostaining for Ki67, a marker of the cell cycle, in tissue samples from epileptic patients.We were unable to find stained cells among the neurons that had migrated out of the granule cell layer, suggesting that in humanepileptic patients, like in kainate-injected mice, granule cell dispersion is not an aberrant migration of young neurons.

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Figure 2 Development of granule cell dispersion induced by unilateral intrahippocampal kainate injection in the adult mouse. Coronal sections ofhippocampus were stained with cresyl violet. (A) Contralateral, non-injected hippocampus displaying the normal histology of the hippocampal forma-tion. (B–D) Ipsilateral hippocampus 7 days (B), 21 days (C) and 6 weeks (D) after kainate injection. A progressive dispersion of the granule cells(arrows) is observed. Note neuronal loss in CA1 (arrowheads), CA3, and hilus. Scale bar: 100 mm; GCL, granule cell layer. Reproduced from Heinrich,C., Nitta, N., Flubacher, A., et al., 2006. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation ofgranule cell dispersion in the epileptic hippocampus. J. Neurosci. 26, 4701–4713; copyright by the Society for Neuroscience.

Epilepsy-Associated Reelin Dysfunction Induces Granule Cell Dispersion in the Dentate Gyrus 3

Reelin’s Role in the Development of GCD

As mentioned above, reelin expression was found to be decreased in tissue samples from epileptic patients. This finding pointed toa role of reelin in granule cell lamination, reminiscent of the lamination defects seen in the mouse mutant lacking reelin. However,the dispersed granule cells in the reeler mouse represent a maldevelopment of the granule cell layer, whereas GCD in epilepticpatients appears to be a secondary effect associated with seizure activity. Numerous studies have shown that reelin is a moleculeimportant for the normal development of cell and fiber layers in the hippocampus. However, it is less clear how one might explaina decreased reelin expression in tissue samples of adult epileptic patients.

Animals with unilateral injections of kainate appeared useful in studies of reelin expression associated with GCD. On thekainate-injected side, where GCD developed, we found a dramatic decrease in reelin expression in quantitative real-time RT-PCR studies and by counting reelin mRNA-expressing cells using in situ hybridization (Fig. 3). On the contralateral side,where no granule cell dispersion developed, reelin expression was normal when compared with naïve control animals. Thefindings point to a close relation between reelin expression and the development of GCD, but did not elucidate theunderlying mechanisms.

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Figure 3 Time course of reelin mRNA expression in the mouse hippocampus after unilateral intrahippocampal kainate injection. Reelin mRNAexpressing neurons were localized by in situ hybridization histochemistry. (A) Contralateral hippocampus. Many reelin mRNA-positive neurons arepresent in CA1, CA3, in the hilus, and along the hippocampal fissure. (B) Ipsilateral hippocampus of a saline-injected control mouse 2 days afterinjection. The distribution of reelin mRNA-positive neurons is similar to that in (a). (C–F) Ipsilateral hippocampus 2 days (C), 7 days (D), 2 weeks(E) and 6 weeks (F) after kainate injection. (C) A dramatic reduction of reelin mRNA expression is evident all over the hippocampus 2 days afterkainate injection. Except a few labeled cells, which are still present along the hippocampal fissure, no reelin mRNA-positive neurons can be detectedin CA1 and in the hilus. (D) Seven days after kainate injection, a few reelin mRNA-positive neurons can be observed along the hippocampal fissure(arrows). (E, F) Numbers of reelin mRNA expressing cells remain low along the hippocampal fissure after two (E) and six (F) weeks following kainateinjection, in parallel with a progressive development of GCD. GCL, granule cell layer. Scale bars: A–F, 100 mm. Reproduced from Heinrich, C.,Nitta, N., Flubacher, A., et al., 2006. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granulecell dispersion in the epileptic hippocampus. J. Neurosci. 26, 4701–4713; copyright by the Society for Neuroscience.


Reelin Keeps Adult Granule Cells in Register

The CR-50 antibody against reelin has proven its usefulness in blocking reelin function in a variety of experimental paradigms.Working with the concept that a decreased reelin expression induces an aberrant migration of granule cells (similar to the aberrantmigration of these neurons in reeler mutants), we reasoned that blocking reelin function should lead to granule cell dispersion. Wethus used adult naïve mice that received unilateral infusions of CR-50 antibody into one hippocampus via osmotic minipumps for1 week. For controls, unspecific IgG was infused. On the side of CR-50 infusion, we observed a significant development of GCD nearthe infusion site; no development of GCDwas observed when unspecific IgG was injected. The results were quantified by measuringthe thickness of the granule cell layer and comparing the infused hippocampus with the contralateral one. While no statisticallysignificant differences were observed between the contralateral hippocampus and the ipsilateral hippocampus when unspecificIgG was infused, the thickness of the granule cell layer had significantly increased on the side of CR-50 injection (Fig. 4). Theseresults clearly show that the expression of reelin is not only required for the normal development of dentate lamination but forthe maintenance of a compact granule cell layer in the adult brain.

Summary and Conclusions

Correlating the results of studies on tissue samples from epileptic patients and in experimental animals and mouse mutants shedslight on the mechanisms leading to granule cell dispersion in epilepsy. A similar loss in granule cell lamination in reelermutants andin human GCD prompted our study of reelin expression in tissue samples from patients. The decreased reelin expression weobserved in human GCD led us to study reelin expression in an animal model of epilepsy. We found both a decreased reelin expres-sion and GCD only on the side of kainate injection (not on the contralateral control side). Interestingly, there was ongoing postnatalneurogenesis on the contralateral side, but a cessation of neurogenesis on the kainate-injected side. From these findings, weconcluded that injection of the glutamate agonist kainate induced seizure activity associated with GCD, paralleled by a decreasedreelin expression. A causal link between the development of GCD and decreased reelin expression was found in our experimentswith antibodies neutralizing reelin. Infusion of CR-50 antibody, but not of unspecific IgG, was sufficient to induce GCD in adult,naïve mice.

In summary, we propose the following scenario for the development of GCD:

1. Seizure activity in epileptic patients, or in experimental animals induced by unilateral kainate injections, interferes with reelinexpression.

2. The decreased reelin expression in adult animals or human patients allows mature granule cells to invade the molecular layerand the hilus. This result is consistent with a “stop signal function” of reelin. Reelin-expressing Cajal-Retzius cells in the marginalzone of the neocortex and in the molecular layer of the dentate gyrus prevent migrating neurons from invading these zonesduring development; in the hilus of the dentate gyrus reelin-expressing interneurons might be involved. In reelermutants lackingreelin, but not in wild-type animals, the marginal zone of the neocortex is densely populated by neurons, and in the dentategyrus the granule cells are dispersed and their characteristic dense packing is lost. Reelin appears to have a similar function in theadult organism: Decreased reelin expression, and thus a loss of the “stop signal”, allows granule cells to change their positions.These aberrantly “migrating” cells were not, in our studies, newly generated neurons but differentiated granule cells.

3. A more general conclusion from these studies is that there are molecules, such as reelin, which are important for the maintenanceof the structural organization of the brain. Their malexpression may result in secondary structural changes such as granule celldispersion. It is tempting to speculate that not only seizure activity, but also a variety of other noxious stimuli, may interfere withreelin expression (or with the expression of other control genes) and lead to structural changes in the adult brain that arereminiscent of developmental defects and contribute to neurological or psychiatric diseases.

Future Directions

Our results have shown that reelin is important for the maintenance of the laminated organization of the dentate gyrus. In epilepticpatients with decreased reelin expression, in kainate-injected mice, and in the reelin-deficient mutant reeler, dentate granule cells donot form a compact cell layer but are dispersed. Can the application of reelin rescue granule cell dispersion?

Using slice cultures of reeler mutants as a model, we were able to show that the scattered distribution of the granule cells can berescued by wildtype cocultures. Based on these findings, we have treated kainate-injected mice with infusions of recombinant reelin.As described, mice with unilateral injections of kainate develop epileptic seizures and show decreased reelin expression and granulecell dispersion on the injected side but not on the contralateral side. Following treatment with recombinant reelin we indeedobserved a reduced granule cell dispersion, but there is a long way ahead before we will know whether or not reelin treatmentmay open up a new therapeutic avenue.

The results reported here have shown that reelin expression is sensitive to epileptic activity. There may be other noxious factorsthat interfere with the expression of reelin or other molecules important for the maintenance of normal network structure and func-tion. Along this line, it needs to be determined by molecular approaches in which way reelin expression is regulated. Moreover, ourrecent studies using a conditional reelin knockout mouse revealed that the mere loss of reelin in the adult hippocampus is not


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Figure 4 Effect of chronic CR-50 antibody infusion into the dentate gyrus of adult mice. Antibodies were chronically administered by osmoticpumps inserted in the right hippocampus over a period of 7 days followed by another 7 days of survival. Morphological changes were visualized bycresyl violet staining. Infusion of CR-50 resulted in a massive increase in the width of the granule cell layer (B, D) as compared to the contralateralside (A, C). The widening of the granule cell layer was confined to the site of injection, indicating that a local neutralization of reelin altered the lami-nation of adult granule cells. No change in lamination was observed after infusion of mouse control IgG (E, F). (E) Contralateral side. (F) Side of IgGinfusion. Scale bars: A, B, E, F: 150 mm; C, D: 40 mm. (G) Quantitative evaluation of GCL width in CR-50 (n ¼ 6) and IgG-infused hippocampi(n ¼ 5). The width of the GCL was measured in the ipsi- and contralateral hippocampus in five sections/animal, and five measurements were takenper hippocampus. Mean values � S.E.M. are shown. In the CR-50-injected animals, the width of the GCL was significantly increased as compared tothe contralateral side (p < 0.0277) using the two sample Wilcoxon rank-sum test. Comparisons were of the unpaired two-sided type. Reproducedfrom Heinrich, C., Nitta, N., Flubacher, A., et al., 2006. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie theformation of granule cell dispersion in the epileptic hippocampus. J. Neurosci. 26, 4701–4713; copyright by the Society for Neuroscience.


sufficient to induce GCD in a dentate gyrus that underwent normal development but was then subjected to reelin deficiency. Addi-tional mechanisms might be involved such as yet unknown signaling cascades activated by neuronal overexcitation in humanepilepsy and experimental epilepsy in animals. Similarly, changes in the proteolytic processing of reelin might play a role. Infact, there is recent evidence from our laboratories showing that proteolytic processing of reelin is impaired under epileptic condi-tions and contributes to the development of GCD. Finally, future studies need to address the effects of reelin signaling on cytoskel-etal reorganization which is required for the actual migration process. In spite of increasing knowledge about the signaling cascadeactivated by reelin binding to its receptors, very little is known about the ways in which reelin acts on the cytoskeleton to control cellmovement and arrest, respectively.

Further Reading

Bouilleret, V., Ridoux, V., Depaulis, A., et al., 1999. Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: electroencephalography,histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience 89, 717–729.

Chai, X., Münzner, G., Zhao, S., et al., 2014. Epilepsy-induced motility of differentiated neurons. Cereb. Cortex 24, 2130–2140.D’Arcangelo, G., Miao, G.G., Chen, S.C., et al., 1995. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374, 719–723.Drakew, A., Deller, T., Heimrich, B., et al., 2002. Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice. Exp. Neurol. 176, 12–24.Fahrner, A., Kann, G., Flubacher, A., et al., 2007. Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp. Neurol. 203,

320–332.Förster, E., Zhao, S., Frotscher, M., 2006. Laminating the hippocampus. Nat. Rev. Neurosci. 7, 259–267.Frotscher, M., 1998. Cajal-Retzius cells, reelin and the formation of layers. Curr. Opin. Neurobiol. 8, 570–575.Haas, A., Frotscher, M., 2004. Migration disorders and epilepsy. In: Herdegen, T., Delgado-García, J.M. (Eds.), Brain. Damage and Repair. Kluwer Academic Publishers, Dordrecht,

pp. 391–402.Haas, C.A., Dudeck, O., Kirsch, M., et al., 2002. Role for reelin in the development of granule cell dispersion in temporal lobe epilepsy. J. Neurosci. 22, 5797–5802.Häussler, U., Bielefeld, L., Froriep, U.P., et al., 2012. Septotemporal position in the hippocampal formation determines epileptic and neurogenic activity in temporal lobe epilepsy.

Cereb. Cortex 22, 26–36.Heinrich, C., Nitta, N., Flubacher, A., et al., 2006. Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in

the epileptic hippocampus. J. Neurosci. 26, 4701–4713.Houser, C.R., 1990. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res. 535, 195–204.Jessberger, S., Römer, B., Babu, H., Kempermann, G., 2005. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp. Neurol. 196,

342–351.Kralic, J.E., Ledergerber, D.A., Frischy, J.-M., 2005. Disruption of the neurogenic potential of the dentate gyrus in a mouse model of temporal epilepsy with focal seizures. Eur. J.

Neurosci. 22, 1916–1927.Lane-Donovan, C., Philips, G.T., Wasser, C.R., et al., 2015. Reelin protects against amyloid b toxicity in vivo. Sci. Signal. 8, ra67.Müller, M.C., Osswald, M., Tinnes, S., et al., 2009. Exogenous reelin prevents granule cell dispersion in experimental epilepsy. Exp. Neurol. 216, 390–397.Nakajima, K., Mikoshiba, K., Miyata, T., et al., 1997. Disruption of hippocampal development in vivo by CR-50 mAb against reelin. Proc. Natl. Acad. Sci. U.S.A. 94, 8196–8201.Ogawa, M., Miyata, T., Nakajima, K., et al., 1995. The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons.

Neuron 14, 899–912.Parent, J.M., Yu, T.W., Leibowitz, R.T., et al., 1997. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat

hippocampus. J. Neurosci. 17, 3727–3738.Stanfield, B.B., Cowan, W.M., 1979. The morphology of the hippocampus and dentate gyrus in normal and reeler mice. J. Comp. Neurol. 185, 393–422.Tinnes, S., Ringwald, J., Haas, C.A., 2013. TIMP-1 inhibits the proteolytic processing of Reelin in experimental epilepsy. FASEB J. 27, 2542–2552.Tinnes, S., Schäfer, M.K., Flubacher, A., et al., 2011. Epileptiform activity interferes with proteolytic processing of Reelin required for dentate granule cell positioning. FASEB J. 25,

1002–1013.Zhao, S., Chai, X., Förster, E., Frotscher, M., 2004. Reelin is a positional signal for the lamination of dentate granule cells. Development 131, 5117–5125.


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