Hippocampal kindling increases the expression of glutamate receptor-A flip and -B flip mRNA in dentate granule cells

Kamphuis, Willem; Monyer, Hannah; Rijk, T. C. De; Silva, F. H. Lopes da

doi:10.1016/0304-3940(92)90802-e

Cited by 66 publications

(22 citation statements)

References 20 publications

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“…Changes in splice variant ratios have been suggested to play a role in certain pathophysiological phenomena. In rat hippocampus, a significant upregulation of GIuR-A flip and GluR-B flip mRNA was observed after kindling [4]. A similar transient elevation of GluR-B flip was reported in hippocampus of rats with kainate-induced epilepsy [5].…”

Section: Introductionsupporting

confidence: 72%

Alternative splicing of AMPA receptor subunits: regulation in clonal cell lines

Christnacher¹,

Sommer²

1995

FEBS Letters

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Section: Introductionsupporting

confidence: 72%

Alternative splicing of AMPA receptor subunits: regulation in clonal cell lines

Christnacher¹,

Sommer²

1995

FEBS Letters

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“…This slow time course of most splicing responses is compatible with longer-term changes in neuronal activity, such as circadian modulation of excitation, or circuit consolidation during development. Many splicing events, including NR1 exon 5, are seen to change during critical periods of circuit refinement in postnatal development, or in response to chronic stimuli such as kindling or other induced seizures in adult animals (Kamphuis et al 1992;Laurie and Seeburg 1994;Kraus et al 1996;Wang and Grabowski 1996;Rafiki et al 1998;Ying et al 1998;Daoud et al 1999;Hoffmann et al 2000;Musshoff et al 2000;Yin et al 2001;Bottai et al 2002;Llansola et al 2005;Jaekel et al 2006). The role of Fox-mediated alternative splicing in modulating changes in membrane physiology during these processes thus invites further study.…”

Section: Discussionmentioning

confidence: 99%

An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

Lee¹,

Tang²,

Black³

2009

Genes Dev.

142

151

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Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in the initial phase of chronic depolarization. The splicing of many neuronal transcripts is also regulated by members of the Fox (Feminizing gene on X) protein family, and these Fox targets are also often proteins affecting synaptic activity. We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated in a variety of neurological diseases, can counteract the effects of chronic depolarization on splicing. We find that exon 19 of Fox-1 is itself repressed by depolarization. Fox-1 transcripts missing exon 19 encode a nuclear isoform of Fox-1 that progressively replaces the cytoplasmic Fox-1 isoform as cells are maintained depolarizing media. The resulting increase in nuclear Fox-1 leads to the reactivation of many Fox-1 target exons, including exon 5 of the NMDA receptor 1, that were initially repressed by the high-KCl medium. These results reveal a novel mechanism for the slow modulation of splicing as cells adapt to chronic stimuli: The subcellular localization of a splicing regulator is controlled through its own alternative splicing. Alternative pre-mRNA splicing is an important mechanism for controlling gene expression in metazoan organisms. Changes in splice site or exon usage frequently determine the function of a gene product or eliminate its expression (Black 2003;Matlin et al. 2005;Blencowe 2006). The best understood systems of splicing regulation are those modulated by cell type, where stable differences in pre-mRNA-binding protein expression determine a splicing choice. However, splicing is also dynamically regulated by external stimuli and growth conditions. Most cellular signaling pathways that alter gene transcription also alter groups of alternative exons (Shin and Manley 2004;Blaustein et al. 2007;Stamm 2008). In some cases, these responses have been traced to particular regulatory elements in the pre-mRNA, to post-translational modifications of splicing regulators, or to changes in transcriptional control. However, the mechanisms that allow the splicing machinery to respond to dynamic stimuli are not well understood.A particularly interesting regulatory mechanism in excitable cells is their response to membrane depolarization. Depolarization-induced changes in neuronal transcription are well studied and involve the activation of CaM kinase and other signaling pathways to induce transcription of both rapid primary response genes and more slowly developing secondary responses (Flavell and Greenberg 2008;Greer and Greenberg 2008). These transcriptional programs play important roles in neuronal plasticity and modulating synaptic activation. Ion channel mRNAs and other transcripts affecting membrane activity also often contain exons whose splicing responds to chronic depolar...

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“…However, an alternate possibility is that spontaneous limbic seizures could alter glutamate receptor subunits. Recent studies indicate that following acute reactive seizures, ionotropic glutamate receptor mRNA levels change within minutes to hours, remain altered for hours to days, and occur in the absence axon sprouting (Gall et al, 1990;Kamphuis et al, 1992;Friedman et al, 1994;Gold et al, 1996;Lason et al, 1997). It is therefore unclear whether chronic limbic seizures show alterations in glutamate receptor subunits similar to those observed after acute reactive seizures and/or whether the changes in ionotropic glutamate receptor subunits correlate with aberrant mossy fiber sprouting.…”

Section: Introductionmentioning

confidence: 94%

Hippocampal AMPA and NMDA mRNA levels correlate with aberrant fascia dentata mossy fiber sprouting in the pilocarpine model of spontaneous limbic epilepsy

et al. 1998

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There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axon circuits should alter postsynaptic glutamate receptor properties. In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-methyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated with mossy fiber sprouting. Sprague-Dawley rats were injected with pilocarpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seizures (day 25; n = 7); and (3) chronic seizure phase after many seizures (day 85; n = 9). Hippocampi were studied for neuron counts, inner molecular layer (IML) neo-Timm's staining, and GluR1-3 and NMDAR1-2b mRNA levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater CA4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densities; (2) early seizure phase showed increased FD GluR3, increased CA1 NMDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seizure phase showed increased FD GluR2; increased FD and CA4 GluR3; decreased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDAR2b levels. In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seizure phase and (2) certain subunit alterations correlated with mossy fiber sprouting. Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis.

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Hippocampal kindling increases the expression of glutamate receptor-A flip and -B flip mRNA in dentate granule cells

Cited by 66 publications

References 20 publications

Alternative splicing of AMPA receptor subunits: regulation in clonal cell lines

Alternative splicing of AMPA receptor subunits: regulation in clonal cell lines

An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

Hippocampal AMPA and NMDA mRNA levels correlate with aberrant fascia dentata mossy fiber sprouting in the pilocarpine model of spontaneous limbic epilepsy

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