Immature-like astrocytes are associated with dentate granule cell migration in human temporal lobe epilepsy

doi:10.1016/S0304-3940(02)00718-8

Neuroscience Letters

Volume 330, Issue 1, 13 September 2002, Pages 114-118

https://doi.org/10.1016/S0304-3940(02)00718-8 Get rights and content

Abstract

In human temporal lobe epilepsy, a dispersion of dentate granule cells is frequently described in adults who had an early risk factor. To elucidate the role of glia in this phenomenon, we investigated neuronal dispersion, astrocyte organization and expression of intermediate filaments of mature and immature astrocytes (i.e. glial fibrillary acidic protein (GFAP) and vimentin, respectively) in seven subjects with early febrile seizures (F(+)) and five subjects with other etiologies than febrile seizures (F(−)). Compared to F(−) patients, a majority of F(+) subjects showed neuronal dispersion and vimentin expression in radial glia. However, in two patients with the maximal dispersion, radial processes expressed only GFAP. We suggest that granule cell migration that occurs in adult epileptic focus results from the transient occurrence of immature-like glia throughout the granular layer.

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Acknowledgements

We thank F. de Bock, L. Charvet, and M. Passama for image processing and iconography and N. Lautrédou-Audouy for confocal microscopy at the C.R.I.C.

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Granule cell dispersion (GCD) in the dentate gyrus is a frequent feature of Ammon's horn sclerosis (AHS) which is often associated with temporal lobe epilepsy (TLE). It has been hypothesized that GCD may be caused by an abnormal migration of newly born granule cells. To test this hypothesis, we used markers of proliferation and neurogenesis and immunocytochemical methods as well as quantitative Western blot and real-time RT-PCR analyses in surgically resected hippocampi from TLE patients and controls. Below the age of 1 year, Ki-67-immunopositive nuclei were detected in the subgranular zone of the dentate gyrus, but not in the dentate of TLE patients independent of age. The expression of the proliferation marker minichromosome maintenance protein 2 (mcm2) and of doublecortin (DCX) decreased significantly with age in controls and in TLE patients, but the expression of both proteins was independent of the degree of AHS and GCD. Quantitative real-time RT-PCR confirmed these findings at the level of gene expression. In contrast, immunocytochemistry for glial fibrillary acidic protein (GFAP) and vimentin as well as Golgi staining revealed a radially aligned glial network in the region of GCD. GFAP-positive fiber length significantly increased with the severity of GCD. These results indicate that epileptic activity does not stimulate neurogenesis in the human dentate gyrus and that GCD probably does not result from a malpositioning of newly generated granule cells, but rather from an abnormal migration of mature granule cells along a radial glial scaffold.
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Depuis les années 1960, beaucoup de certitudes concernant la neurogénèse se sont effondrées. À la découverte de la persistance d’une neurogénèse à l’âge adulte chez les mammifères, dont l’homme, s’est ajouté le concept de progéniteurs communs pour les neurones et les astrocytes. C’est ainsi que, de la période embryonnaire à la période adulte, un véritable continuum existe entre les cellules neuroépithéliales, la glie radiaire et les astrocytes, pour assurer la formation de nouveaux neurones et de nouvelles cellules gliales. De très nombreux facteurs, sécrétés in situ ou véhiculés par voie sanguine, régulent la neurogénèse physiologique. Les cibles et le rôle des neurones néoformés sont mal élucidés. Dans certaines conditions pathologiques (ischémie, épilepsie, lésions), la neurogénèse physiologique est amplifiée ; mais son rôle bénéfique ou délétère n’est pas clairement établi. La connaissance des processus qui contrôlent la neurogénèse adulte, qu’elle soit physiologique ou réactionnelle à diverses conditions pathologiques, laisse entrevoir des perspectives thérapeutiques, en améliorant les transplantations par un meilleur contrôle de la différenciation et de la survie des cellules souches, et en contrôlant la neurogénèse « endogène ».
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Citation Excerpt :
Interestingly, in contrast to proliferation, migration does not appear to be symmetrical around the lesion. The vimentin-positive area at the base of the lesion appears to be a preferred migratory route which we propose may be correlated to the intense proximal reactive astrogliosis (vimentin-expressing) with its corresponding production and release of growth factors and cytokines [7,13,15,25,32,44]. Consistent with this migratory role, it has previously been suggested that vimentin-positive reactive adult astrocytes may have similar properties to radial glia, which facilitate migration [6,26,31,40] and serve as a pathway for newly recruited cells, guiding them to the lesion or its proximity.
Vimentin-expressing astrocytes in the adult are commonly associated with the proximal, most reactive gliotic response ultimately leading to the formation of a new glial limitans. It was thought, since vimentin expression and astroglial proliferation are most prominent nearest the lesion site, that vimentin may be a characteristic of immature newly divided astrocytes. We recently established a unique distribution of vimentin-expressing reactive astrocytes at the base of a focal cortical ischemic lesion in rats. The purpose of the present study was to assess the correlation of proliferation and migration with this unique distribution following focal injury. With the use of bromodeoxyuridine (BrdU) and immunohistochemistry for astrocytes and microglia/macrophages, proliferation and migration of cells was shown to be throughout the ipsilateral hemisphere on day one and become progressively more centralized to the lesion by day 3. The vimentin-expressing area at the base of the lesion does not exhibit distinguishable proliferation rates from non-vimentin-expressing regions surrounding the lesion and did not demonstrate obvious double labeling with BrdU⁺ cells, although on occasion vimentin expression is closely associated with BrdU. However, this region did become a focal point for migration into and around the lesion by day 3. Additionally, asymmetrical distribution of vimentin was shown in four different injury models with vimentin⁺ cells always situated between the lesion and the corpus callosum. It is concluded that although vimentin-expressing cells did not correlate with proliferating cells in these focal injury models, perhaps this distinct population of reactive astrocytes serve as a source of cytokines or as a physical conduit for migrating cells from distant sites through the corpus callosum.

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Immature-like astrocytes are associated with dentate granule cell migration in human temporal lobe epilepsy

Abstract

Section snippets

Acknowledgements

Neuroscience

Trends Neurosci.

Brain Res.

Neurobiol. Dis.

Epilepsy Res.

J. Neurol. Sci.

Trends Pharmacol. Sci.