Differential regulation of basic helix–loop–helix mRNAs in the dentate gyrus following status epilepticus

doi:10.1016/S0306-4522(01)00198-1

Neuroscience

Volume 106, Issue 1, 3 September 2001, Pages 79-88

https://doi.org/10.1016/S0306-4522(01)00198-1 Get rights and content

Abstract

In various chemoconvulsant models of human temporal lobe epilepsy, the induction of epileptogenesis by a prolonged period of continuous seizure activity is accompanied by significant changes in hippocampal structure. These changes include an increase in neurogenesis within the proliferative subgranular zone (SGZ) of the dentate gyrus and induction of mossy fiber sprouting in mature dentate granule cells. As dentate granule cell neurogenesis and axon outgrowth are also hallmarks of hippocampal development, we hypothesized that molecules involved in normal development may also play a role in similar changes associated with epileptogenesis. To begin to test this hypothesis, we have analyzed the expression patterns of multiple members of the basic helix–loop–helix (bHLH) family of transcription factors in both normal and epileptic adult rats. bHLH protein expression has been found recently in dentate granule cells at specific developmental stages, and analysis of developmental models suggests specific neural differentiation functions for these molecules. We show that mRNA expression of all seven bHLH family members examined in this study, as well as the divergent homeobox protein Prox1, is present in the adult. Patterns of expression varied considerably between family members, ranging from the limited expression of Mash1 in the neurogenic SGZ of the dentate gyrus to the scattered, widespread profile of Hes5 throughout the dentate gyrus and the hippocampus proper. Moreover, these varied profiles of expression were differentially regulated following status epilepticus, with some increasing (Mash1, Id2), some falling (Hes5, Prox1), and others remaining mostly unchanged (NeuroD/BETA2, NeuroD2/NDRF, Id3, Rath2/Nex1).

While the function of these molecules in the adult brain remains to be characterized, our findings support the idea that molecules controlling cell-fate decisions in the developing dentate gyrus are also operative during seizure-induced neurogenesis and plasticity.

Section snippets

Induction of SE

All animals were treated according to protocols for animal care established by the University of California, San Francisco, and the National Institutes of Health. All efforts were made to minimize the number of animals used and their suffering. Adult male Sprague–Dawley rats (180–200 g; Bantin and Kingman, Fremont, CA, USA) were given an i.p. injection of atropine methylbromide (5 mg/kg; Sigma, St. Louis, MO, USA) followed 20 min later by an i.p. injection of pilocarpine hydrochloride (340

Multiple patterns of bHLH transcription in normal adult hippocampus

bHLH members such as Mash1, Id2, and Hes5 are likely to be involved in numerous decision points in the differentiation process (Ishibashi et al., 1995, Jen et al., 1997, Kageyama et al., 1997, Horton et al., 1999, Torii et al., 1999). Therefore, although the expression of these bHLH members is well described early in development when they are likely to play a role in maintaining the undifferentiated state of neuronal precursors, it was not surprising to find them expressed in multiple areas of

Discussion

Neurogenesis and axon outgrowth are important aspects of dentate gyrus plasticity associated with both development and SE-induced injury. These parallels raise the possibility that the molecules and mechanisms guiding neurogenesis and axon outgrowth during development overlap with those expressed during epileptogenesis. Consequently, knowledge regarding developmental changes may provide important clues regarding alterations associated with epileptogenesis, and vice versa. Supporting this

Acknowledgements

This work was funded by NIH Grant NS39950 (D.H.L.) and the American Epilepsy Society with support from the Milken Family Foundation (R.C.E.).

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¹: These authors contributed equally to the work described in this paper.

²: Present address: Neurodevelopmental Disorders Laboratory, Department of Neurology, University of California, San Francisco, CA 94143, USA.

³: Present address: Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48104-1687, USA.

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Differential regulation of basic helix–loop–helix mRNAs in the dentate gyrus following status epilepticus

Abstract

Section snippets

Induction of SE

Multiple patterns of bHLH transcription in normal adult hippocampus

Discussion

Acknowledgements

Mech. Dev.

Cell

Neuroscience

Curr. Opin. Neurobiol.

Brain Res.

Brain Res.

Cell

Mol. Cell. Neurosci.

Int. J. Biochem. Cell. Biol.

Curr. Opin. Neurobiol.

Curr. Biol.

Epilepsy Res.

Neuron

Mech. Dev.

Brain Res. Bull.

Neurosci. Lett.

Neuron

Neuron

J. Biol. Chem.

Neurosci. Lett.

Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods

J. Comp. Neurol.

Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells

J. Comp. Neurol.

Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

J. Comp. Neurol.

Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions

J. Comp. Neurol.

Notch signaling: cell fate control and signal integration in development

Science

Development of the hippocampal region in the rat. I. Neurogenesis examined with 3H-thymidine autoradiography

J. Comp. Neurol.

Mash1 regulates neurogenesis in the ventral telencephalon

Development

The pilocarpine model of epilepsy

Ital. J. Neurol. Sci.

Conservation of the Notch signalling pathway in mammalian neurogenesis

Development

Neurogenesis in the adult human hippocampus (see comments)

Nat. Med.

Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus

Epilepsia

Lesion-induced mossy fibers to the molecular layer of the rat fascia dentata: identification of postsynaptic granule cells by the Golgi-EM technique

J. Comp. Neurol.

Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation

J. Neurosci.