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University of Tübingen, Department of Otorhinolaryngology, Hearing Research Center Tübingen, Molecular Neurobiology, Tübingen, Germany
Received September 14, 2007; accepted January 15, 2008
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Abstract |
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). BDNF transcription is stimulated dramatically by membrane depolarization (Ghosh et al., 1994b), neural activity during kindling, or long-term potentiation (Patterson et al., 1992). BDNF has a complex gene structure, and the nomenclature has been altered recently (Aid et al., 2007). Although we published previous work using the old nomenclature system (Rüttiger et al., 2007; Tan et al., 2007), the present work adopts the system of Aid et al. (2007).
The BDNF gene possesses eight 5'-noncoding exons (I-VIII), each of which is independently regulated and can be alternatively spliced to a common 3'-exon (IX), which contains the protein coding sequence (Timmusk et al., 1993; Aid et al., 2007). Each upstream exon is affected by neuron-specific signal transduction mechanisms (West et al., 2001; Aid et al., 2007). Although the individual function of the BDNF transcripts are not yet known, a differential role during plasticity-associated changes of synaptic efficacy has been suggested (Patterson et al., 1992; Thoenen, 2000; West et al., 2001).
We demonstrated recently that the application of the ototoxic drug salicylate results in the up-regulation of BDNF exon IV and VI (previously exons III and IV) in spiral ganglion neurons of the cochlea, and that this up-regulation is associated with changes in cortical gene expression and tinnitus perception (R. Panford-Walsh, W. Singer, L. Rüttiger, S. Hadjab, J. Tan, M. Geisler, U. Zimmerman, I. Köpschall, K. Röhbock, A. Vieljans, et al., submitted). Trauma-induced up-regulation (R. Panford-Walsh, W. Singer, L. Rüttiger, S. Hadjab, J. Tan, M. Geisler, U. Zimmerman, I. Köpschall, K. Röhbock, A. Vieljans, et al., submitted; Tan et al., 2007) and age-related decrease (Rüttiger et al., 2007) of cochlear BDNF levels were discussed as a trigger for pathological plasticity responses in the central auditory system. As such, the elucidation of the mechanisms that participate in the trauma-induced alteration of cochlear BDNF levels may be crucial for future therapeutic designs.
The neuronal responses after systemic application of salicylate are contradictory. Salicylate either reduces (Wallhaüsser-Franke et al., 2003) or increases neuronal firing rates (Evans and Borerwe, 1982; Wallhaüsser-Franke et al., 2003) and exhibits dose-dependent effects (Stypulkowski, 1990). A dose-dependent effect of salicylate has been described to act by potentiating NMDA receptor currents in cortical or spiral ganglion neurons (Peng et al., 2003). Salicylate, however, may also influence cochlear neuron excitability through its inhibitory influence on outer hair cell motility (Grosh et al., 2004), thereby differentially facilitating the excitatory effects of glutamate (Müller et al., 2003). It is most interesting that NMDA receptors and L-type voltage-sensitive Ca2+ channels (L-VSCC), which mediate the calcium-dependent recruitment of distinct transcription factors on BDNF promoters, were both described as being expressed in cochlear neurons (Niedzielski and Wenthold, 1995; Waka et al., 2003).
To date, the promoter of BDNF exons I, IV, and VI have been studied in detail (Tabuchi et al., 2002; Takeuchi et al., 2002; Tao et al., 2002). Within the exon IV promoter, three calcium response elements (CaREs) have been identified (Tao et al., 2002), which are bound by cAMP/Ca2+ response element binding protein (CREB) (Montminy and Bilezikjian, 1987), upstream stimulatory factors 1 and 2 (USF1 and USF2) (Sawadogo and Roeder, 1985), and calcium-response transcription factor 1 (CaRF1) (Tao et al., 2002) in a cooperative manner.
CREB interacts with CaRE3 by binding to the consensus sequence known as cAMP response element (Kornhauser et al., 2002). CREB is prebound in an inactive form and activates the transcription of exon IV after phosphorylation through calmodulin kinase IV (Kornhauser et al., 2002). The heterodimer consisting of USF1 and USF2 (Vallet et al., 1998) binds to CaRE2 (Sawadogo and Roeder, 1985). Finally, CaRE1 is bound in a calcium- and neuron-selective manner by CaRF1, which is known to be expressed in distinct regions of the brain, with the highest expression in the hippocampus (Tao et al., 2002). It is assumed that for normal neuronal plasticity, these transcription factors are expressed at relatively stable levels (Chen et al., 2003b).
Here, we used RT-PCR and in situ hybridization to investigate the expression of CaRF1, USF1/2, and CREB in the cochlea after exposure to salicylate. We observed striking changes not only in BDNF exon IV expression but also in the expression of the transcription factor CaRF1; a dose-dependent effect on gene expression was also observed. Our data show that the expression (as opposed to the activity) of protein factors involved in the regulation of BDNF exon IV transcription is altered. Such a mechanism would dramatically alter the currently accepted view of the BDNF activation during plasticity responses.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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For systemic application, animals received intraperitoneal injections of different concentration of salicylate (aspirin; Sigma, Munich, Germany) (350 and 500 mg/kg body weight) 3 h before sacrifice. Control animals received the corresponding volumes of saline solution.
Tissue Preparation. Before decapitation, animals were asphyxiated with carbon dioxide. Cochleae were then isolated and dissected as described in Knipper et al. (2000). For immunostaining, cochleae were dissected and fixed by injection with 2% paraformaldehyde for 30 min, and the bony part of the lateral wall of the cochlear turns was removed. All cochleae for in situ and for immunohistochemistry were embedded in O.C.T. compound (Miles Laboratories, Elkhart, IN), cryosectioned at 10 µm, and mounted on SuperFrost*/Plus microscope slides at -20°C.
Riboprobe Synthesis and in Situ Hybridization. Antisense and sense primers for the amplification of BDNF exons IV, VI, and IX from rat genomic DNA were constructed as described in Timmusk et al. (1993). For riboprobe synthesis of the CaRE binding proteins, mRNA was isolated from rat hippocampus with the Dynal mRNA Direct Kit (Invitrogen, Karlsruhe, Germany). Reverse transcription was done with Superscript II (Invitrogen). PCR was used to amplify the CaRE binding proteins.
The following primer pairs were used: 1) CREB: 5' TTG ATT CAT GAC CAT GGA CTC TGG CAG 3' and 5' TTG AAT TCT TAA TCT GAC TTG TGG CAG TAA AG 3', accession number NM_134443
[GenBank]
; 2) USF1: 5' ATG AAG GGG CAG CAG AAA ACA G 3' and 5' ACG GCG GTT GTA CTC CCA GAT 3', accession number NM_031777
[GenBank]
; 3) USF2: 5' CAA TGA GCT CCT GAG GCA GCA GAT C 3' and 5' CAC ACA CAC ACG CGC ACA CAT ACA C 3', accession number NM_031139
[GenBank]
; and 4) CaRF1: 5' AAG TTG CAG CCA AGA CTC TCC TC 3' and 5' AGT CAA AAC TGC CCA TCA TCC AC 3', accession number XM_217411. In the PCR reaction, cDNA was denatured for 3 min at 94°C followed by 33 cycles consisting of 1 min at 94°C, 1 min at 55°C, and 1 min at 72°C. A final extension was done at 72°C for 10 min. Riboprobe synthesis was carried out as described in Rüttiger et al. (2007) and Tan et al. (2007).
In situ hybridization was performed as described previously (Wiechers et al., 1999). In brief, after incubating the slides with antidigoxigenin antibody conjugated to alkaline phosphatase (1:750; Roche, Mannheim, Germany), the sections were then allowed to develop in the substrate solution containing nitroblue tetrazolium salt and 5-bromo-4-chloro-3-indolyl phosphate (Sigma). The sections were observed at different time periods to monitor the development of the substrate into a colored product. Sections from controls and treated animals were stopped at the same time, mounted, and viewed using an Olympus AX70 microscope (Olympus, Tokyo, Japan). All experiments were done in duplicate with n = 3 for each group, control and treated animals.
Immunohistochemistry. For immunostaining, slices were washed two times in 50 mM phosphate-buffered saline (1x PBS). Sections were incubated for 30 min in NGS at room temperature. The primary antibody, phospho-CREB (Ser133) (Cell Signaling Technology, Danvers, MA), was diluted 1:50 and incubated on the slices overnight at 4°C. On the second day, sections were washed with 1x PBS three times. Primary antisera were visualized with Cy3 (Jackson ImmunoResearch Laboratories, West Grove, PA), diluted 1:1500, and incubated for 1 h at room temperature in the dark. Slices were washed again three times with 1x PBS. Sections were then mounted in Vectashield mounting medium containing 4,6-diamidino-2-phenylindole nuclear staining (Vector Laboratories, Burlingame, CA) and viewed using an Olympus AX70 microscope. The experiments were done in duplicate with n = 3 for each group, control and treated animals.
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). A reduced number of cycles (27) was initially tested to ensure nonsaturating amplification of GAPDH and cyclophilin and an equivalent usage of cDNAs in both control and treated samples. The PCR primer sequences for BDNF exon IV and GAPDH were as described in Zha et al. (2001). The calcium-response element binding proteins were amplified using the primer pairs described above. Amplification of cyclophilin was accomplished using the following primer sequences: 5' CGT GCT AGC ACT GGG GAG AAA 3' and 5' CAT GCC TTC TTT CAC CTT CCC AAA GAC 3', accession number NM_017101
[GenBank]
. The amplification conditions used for BDNF exon IV and GAPDH were as described in Tan et al. (2007). For CaRF1 and USF1, the amplification program consisted of an initial denaturation phase of 94°C for 3 min, 33 cycles of 1-min denaturation (94°C), 1 min of annealing (61°C), 1.5-min extension (72°C), and a final extension phase of 10 min at 72°C. For USF2 and CREB, an initial denaturation phase of 94°C for 3 min was used, followed by 33 cycles of 30-s denaturation (94°C), 30 s annealing (65°C), 40 s extension (72°C), and a final extension phase of 10 min at 72°C. The PCR products were cloned and sequenced. Densitometric analysis was performed using the Alpha Imager 2200 from Biometra (Göttingen, Germany). The intensity of the amplified band produced for each gene was normalized for each reaction to the coamplified GAPDH or cyclophilin level. Control and treated groups were then compared with each other, and the data were expressed as a mean percentage of control (set at 100%) and standard error of the mean (S.E.M.). Statistical analysis was done using the Student's t test (*, p < 0.05). The number of animals used for statistical analyses was the same within each pair of control and treated animals. For statistical analyses, 3 h after 350 mg/kg salicylate, cochleae from 10 rats were analyzed for BDNF exon IV and CaRF1. Ten rats were analyzed for USF1, USF2, and CREB. The number always indicates animals in each group (control and treated), not the sum of both. For BDNF, exon IV and CaRF1 analysis after dose-dependent application, 10 rats in each group were analyzed. |
Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Tan et al., 2007). We show for the first time the detection of the four transcription factors of BDNF exon IV in spiral ganglion neurons of the mammalian cochlea using RT-PCR (Fig. 1A) and in situ hybridization (Fig. 1 B). Primers were designed for the CaRE binding proteins as described under Materials and Methods. The expected PCR products were amplified with a bp length of 594 bp for CaRF1, 416 bp for USF1, 599 bp for USF2, and 991 bp for CREB (arrows in Fig. 1A). For in situ hybridization, riboprobes were synthesized from the cloned PCR products. Antisense riboprobes specific for BDNF exon IV (data not shown) and the CaRE binding proteins produced positive hybridization signals in the spiral ganglion neurons of the cochlea (Fig. 1B shown for the midbasal turn). No hybridization signals were observed using sense probes (Fig. 1B, insets).
The cochlea is tonotopically organized; i.e., the sensory cells in the apical (top) turn respond specifically to low-frequency sound waves, whereas the sensory cells in the basal (bottom) turn respond to high frequency sound waves. Along the tonotopic axis, BDNF exon IV is expressed in a gradient, with increasing expression in the midbasal/basal turns of the cochlea (Schimmang et al., 2003; Rüttiger et al., 2007). Using sequence-specific riboprobes, we confirmed the tonotopic distribution of BDNF in spiral ganglion neurons of the cochlea (Fig. 2A). A strikingly similar pattern of expression was observed for CaRF1 (Fig. 2 B), with mRNA expression increasing in spiral ganglion neurons of the medial and midbasal/basal turns. In contrast, no significant changes were seen in the expression of CREB, USF1, or USF2 along the tonotopic axis (shown for USF2, Fig. 2C).
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Dose-Dependent Alteration of Activity-Dependent Genes in the Cochlea. To assess in detail the dynamics of CaRF1 expression in spiral ganglion neurons of the cochlea induced by acute salicylate application (Figs. 3 and 4), we used in situ hybridization and RT-PCR to test the effects of 350 and 500 mg/kg salicylate injected intraperitoneally (Fig. 5). For BDNF exon IV, a peak at 350 mg/kg salicylate was observed followed by a decrease at higher salicylate doses shown in spiral ganglion neurons of the medial turn of the cochlea (Fig. 5, A and C). Likewise, CaRF1 expression was significantly up-regulated 3 h after injection of 350 mg/kg salicylate but was decreasing at higher doses of salicylate (Fig. 5, B and D). No changes in gene expression were observed for USF1, USF2, or CREB using various doses of salicylate (data not shown).
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), the impact of salicylate on the phosphorylation of CREB in spiral ganglion neurons was tested. In a preliminary experiment, a change in phosphorylation of CREB after salicylate injection (350 mg/kg) (Supplemental Fig. S1, red staining) is shown by immunohistochemistry. An antibody against phospho-CREB (Ser133) was used for these experiments. A tonotopic phospho-CREB expression gradient was observed in the nuclei of spiral ganglion neurons in control animals (Supplemental Fig. S1A, left column, red staining). The highest number of phospho-CREB immunopositive cells was noted in untreated animals in the most apical cochlear turn, which perceives low frequencies (Supplemental Fig. S1A, top left image, red staining). This gradient was surprisingly the reverse of that normally seen for BDNF exon IV and CaRF1 (Fig. 2, A and B). After salicylate treatment, the phosphorylation of CREB was particularly increased in the nuclei of spiral ganglion neurons of the most basal, high-frequency-generating cochlear turns in comparison with control animals (Supplemental Fig. S1A, bottom images, and B). Although more detailed and quantitative data are required, it seems that the number of phospho-CREB-positive cells in more apical cochlear turns remained unchanged (Supplemental Fig. S1A). Higher magnification of spiral ganglion neurons of the basal cochlear turn underlined the strong increase in CREB phosphorylation (Supplemental Fig. S1B, red staining, arrows). Up-regulation of phospho-CREB in the basal/midbasal cochlear turns is in accordance with the mRNA expression of BDNF exon IV and CaRF1 in the basal turn of the cochlea and the mRNA up-regulation after salicylate treatment in this area (Figs. 2, A and B, and 3, A and B). |
Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). BDNF transcription is regulated by neuronal activity (Shieh and Ghosh, 1999); up-regulation of BDNF expression was first seen after experimentally induced seizure (Isackson et al., 1991). An increase was also seen in vivo after sensory stimulation and in vitro after neuronal activity, suggesting that neuronal activity affects BDNF regulation (Ghosh and Greenberg, 1995). Furthermore, BDNF exon IV is expressed in the auditory system, and its expression is known to be affected by exposure to salicylate (Panford-Walsh et al., submitted).
Although the expression of the transcription factors of BDNF exon IV is presumed to be relatively stable (Chen et al., 2003a), we found here that the expression of the transactive elements of the BDNF exon IV promoter is regulated in an activity-dependent manner. The exact mechanism of regulation of these element is still unclear, although it is well known that depolarization and the subsequent Ca2+ influx induces BDNF exon IV transcription via pre-existing transcription factors (West et al., 2001).
In this study, we investigated the expression of BDNF exon IV and its transcription factors in the spiral ganglion neurons of the mammalian cochlea in response to injection of concentrated salicylate. We showed that salicylate is able to induce an alteration not only in BDNF exon IV expression but also in the expression of its transcription factors. Three hours after injection, an up-regulation of BDNF exon IV and CaRF1 was observed in spiral ganglion neurons (Figs. 3 and 4), suggesting that CaRF1 plays an important role in the regulation of BDNF exon IV expression in the cochlea. Furthermore, the changes in gene expression are dependent on the dose of salicylate given (Fig. 5).
A dose-dependent effect of salicylate has been described to act by potentiating NMDA receptor currents in cortical (Vane et al., 1998) or cochlear neurons (Peng et al., 2003). The experimental conditions used may thus act through changes in glutamate or NMDA receptors, which initiate the calcium-dependent recruitment of transcription factors known to act on BDNF exon IV (Shieh and Ghosh, 1999).
Activity-dependent transcription subsequent to Ca2+ influx affects the different promoters of BDNF (Kim et al., 2001). There are different ways in which calcium can enter the cell, but not all lead to equivalent activation of down-stream gene expression. Calcium entry via NMDA and 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, glutamate receptors, or release from intracellular Ca2+ stores are not sufficient to induce BDNF expression (Ghosh et al., 1994a). Only calcium influx through VSCCs increases BDNF expression and subsequent cell survival (Ghosh et al., 1994a; Tao et al., 2002).
In agreement with the current view that glutamate is the afferent neurotransmitter of hair cells, acting on defined glutamate receptors (Puel, 1995), salicylate was shown recently to potentiate glutamate-mediated currents in cochlear neurons (Peng et al., 2003). This would directly lead to a change in the opening kinetics of voltage-dependent L-type Ca2+ channels. Considering that up- or down-regulation of BDNF is dependent on the degree of stimulation (Tabuchi et al., 2000), we suggest that the observed dose-dependent effects of salicylate on CaRF1 described in the present study may result from an indirect dose-dependent effect of salicylate on L-type Ca2+ channels in cochlear neurons. These changing Ca2+-signaling events can lead to activation of Ca2+/calmodulin-dependent protein kinases, which cause an up-regulation of BDNF mRNA expression (Zafra et al., 1992). It is currently presumed that these in vivo Ca2+-signaling cascades do not in parallel act on the expression of CaRE binding proteins because they are supposed to be expressed relatively stable in the cell. The changes in CaRF1 expression after salicylate application presented in this study, however, indicate that the stability of transacting factors may not be a general rule.
In line with the previous view, the current data indicate that the transcription factors CREB, USF1, and USF2 show no changes in gene expression after injection of concentrated salicylate. A possible explanation could be that they are prebound in an inactive state to the BDNF promoter. Upon a specific activation event, they would then presumably assist in the initiation of transcription. Indeed, it has been shown that USF1/2 are present in unstimulated and membrane-depolarized cells (Chen et al., 2003b) and that the DNA binding activity of the USFs to the BDNF exon IV promoter is not regulated by Ca2+ influx (Chen et al., 2003b).
CREB is known to be prebound to the BDNF exon IV promoter in an inactive form (West et al., 2001). Ca2+ influx leads to phosphorylation of CREB at Ser133, followed by recruitment of the CREB binding protein, which acts as a transcriptional coactivator (West et al., 2001). The localization of CREB is not influenced by the intracellular Ca2+ level (West et al., 2001). Thus, the nonresponsiveness of CREB mRNA in cochlear neurons to various concentrations of salicylate treatment documented in the present study is not surprising. It is also shown that an increase in the phosphorylation of CREB protein after salicylate injection (Supplemental Fig. S1) takes place specifically in the spiral ganglion neurons of those cochlear turns in which BDNF exon IV mRNA is up-regulated after salicylate treatment. This supports the notion that the phosphorylation of CREB, by either CaMKs or cAMP-dependent protein kinase (Zha et al., 2001), may be involved in the signaling pathway that is initiated in spiral ganglion neurons after salicylate treatment. In further studies, the phosphorylation mechanism of CREB and its involvement in transcriptional events of BDNF in spiral ganglion neurons should be analyzed in detail.
In vitro studies with embryonal cortical cells did already point to CaRF1 being regulated in a calcium- and neuron-selective manner similar to BDNF exon IV (Tao et al., 2002). It has been shown that CaRF1 expression is only affected by Ca2+ influx through L-VSCCs, consistent with the hypothesis that CaRF1 drives the calcium-dependent regulation of BDNF. CaRF1 expression is highest in the brain, although it is also expressed at low levels in non-neuronal tissue. CaRF1 expression in the brain is seen in areas in which activity-dependent BDNF exon IV transcripts occur. Thus, the expression pattern of CaRF1 is consistent with its role in regulation of BDNF exon IV transcription (Tao et al., 2002). Considering these observations, we may suggest a similar scenario for CaRF1 and BDNF exon IV in cochlear neurons subsequent to salicylate treatment.
Our hypothesis is that moderate degrees of injury lead to enhancement of Ca2+ levels in cochlear neurons (e.g., by lower and medium concentrations of salicylate or moderate noise trauma, < 100 dB) and may induce a correspondent dose-dependent up-regulation of CaRF1, whereas higher degrees of injury lead to higher increases in Ca2+ levels in cochlear neurons (e.g., via salicylate >500 mg/kg of body weight or acoustic trauma >120 dB) and may induce an opposite (decline) effect on CaRF1. Ca2+-imaging studies in cochlear neurons subsequent to various degree of acoustic trauma and various doses of salicylate may be required, however, to verify this concept.
The data in the present study show that injection of concentrated salicylate, which is known to induce tinnitus in humans and rodents, has an effect not only on the expression of BDNF exon IV but also on the expression of its transcription factors. Although CREB, USF1, and USF2 do not show any changes in their expression pattern after salicylate treatment, CaRF1 is clearly up-regulated in a dose-dependent manner. This suggests that CaRF1 is a crucial component of BDNF exon IV transcription. Bound as the last of the three transcription factors, CaRF1 could be responsible for the regulation of BDNF expression under different trauma conditions. Further studies must be done to distinguish between the degrees of injury, which cause effects in BDNF exon IV and CaRF1 expression.
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Footnotes |
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W.S. and R.P.-W. contributed equally to this work.
ABBREVIATIONS: BDNF, brain-derived neurotrophic factor; CaRF1, calcium response transcription factor 1; USF, upstream stimulatory factor; CREB, cAMP/Ca2+ response element binding protein; CaRE, calcium response element; PCR, polymerase chain reaction; RT-PCR, reverse-transcriptase polymerase chain reaction; NMDA, N-methyl-D-aspartate; L-VSCC, L-type voltage-sensitive Ca2+ channel; PBS, phosphate-buffered saline; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; bp, base pair(s).
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. 
Address correspondence to: Dr. Marlies Knipper, HNO-Klinik, Universität Tübingen, Elfriede-Aulhorn-Straβe 5, D-72076 Tübingen, Germany. E-mail: marlies.knipper{at}uni-tuebingen.de
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References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R, and Greenberg ME (2003a) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302: 885-889.
Chen WG, West AE, Tao X, Corfas G, Szentirmay MN, Sawadogo M, Vinson C, and Greenberg ME (2003b) Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons. J Neurosci 23: 2572-2581.
Evans EF and Borerwe TA (1982) Ototoxic effects of salicylates on the responses of single cochlear nerve fibres and on cochlear potentials. Br J Audiol 16: 101-108.[Medline]
Ghosh A, Carnahan J, and Greenberg ME (1994a) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263: 1618-1623.
Ghosh A, Ginty DD, Bading H, and Greenberg ME (1994b) Calcium regulation of gene expression in neuronal cells. J Neurobiol 25: 294-303.[CrossRef][Medline]
Ghosh A and Greenberg ME (1995) Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science 268: 239-247.
Grosh K, Zheng J, Zou Y, de Boer E, and Nuttall AL (2004) High-frequency electro-motile responses in the cochlea. J Acoust Soc Am 115: 2178-2184.[CrossRef][Medline]
Isackson PJ, Huntsman MM, Murray KD, and Gall CM (1991) BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron 6: 937-948.[CrossRef][Medline]
Kim DS, Lee SJ, and Cho HJ (2001) Differential usage of multiple brain-derived neurotrophic factor promoter in rat dorsal root ganglia following peripheral nerve injuries and inflammation. Brain Res Mol Brain Res 92: 167-171.[CrossRef][Medline]
Knipper M, Zinn C, Maier H, Praetorius M, Rohbock K, Kopschall I, and Zimmermann U (2000) Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral and central auditory systems. J Neurophysiol 83: 3101-3112.
Kornhauser JM, Cowan CW, Shaywitz AJ, Dolmetsch RE, Griffith EC, Hu LS, Haddad C, Xia Z, and Greenberg ME (2002) CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron 34: 221-233.[CrossRef][Medline]
Lauterborn JC, Rivera S, Stinis CT, Hayes VY, Isackson PJ, and Gall CM (1996) Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: evidence for immediate-early gene responses from specific promoters. J Neurosci 16: 7428-7436.
Montminy MR and Bilezikjian LM (1987) Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature 328: 175-178.[CrossRef][Medline]
Müller M, Klinke R, Arnold W, and Oestreicher E (2003) Auditory nerve fibre responses to salicylate revisited. Hear Res 183: 37-43.[CrossRef][Medline]
Niedzielski AS and Wenthold RJ (1995) Expression of AMPA, kainate, and NMDA receptor subunits in cochlear and vestibular ganglia. J Neurosci 15: 2338-2353.[Abstract]
Patterson SL, Grover LM, Schwartzkroin PA, and Bothwell M (1992) Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9: 1081-1088.[CrossRef][Medline]
Peng BG, Chen S, and Lin X (2003) Aspirin selectively augmented N-methyl-D-aspartate types of glutamate responses in cultured spiral ganglion neurons of mice. Neurosci Lett 343: 21-24.[CrossRef][Medline]
Puel JL (1995) Chemical synaptic transmission in the cochlea. Prog Neurobiol 47: 449-476.[CrossRef][Medline]
Rüttiger L, Panford-Walsh R, Schimmang T, Tan J, Zimmermann U, Rohbock K, Kopschall I, Limberger A, Müller M, Fraenzer JT, et al. (2007) BDNF mRNA expression and protein localization are changed in age-related hearing loss. Neurobiol Aging 28: 586-601.[CrossRef][Medline]
Sawadogo M and Roeder RG (1985) Interaction of a gene-specific transcription factor with the adenovirus major late promoter upstream of the TATA box region. Cell 43: 165-175.[CrossRef][Medline]
Schimmang T, Tan J, Müller M, Zimmermann U, Rohbock K, Kopschall I, Limberger A, Minichiello L, and Knipper M (2003) Lack of Bdnf and TrkB signalling in the postnatal cochlea leads to a spatial reshaping of innervation along the tonotopic axis and hearing loss. Development 130: 4741-4750.
Shieh PB and Ghosh A (1999) Molecular mechanisms underlying activity-dependent regulation of BDNF expression. J Neurobiol 41: 127-134.[CrossRef][Medline]
Stypulkowski PH (1990) Mechanisms of salicylate ototoxicity. Hear Res 46: 113-145.[CrossRef][Medline]
Tabuchi A, Nakaoka R, Amano K, Yukimine M, Andoh T, Kuraishi Y, and Tsuda M (2000) Differential activation of brain-derived neurotrophic factor gene promoters I and III by Ca2+ signals evoked via L-type voltage-dependent and N-methyl-D-aspartate receptor Ca2+ channels. J Biol Chem 275: 17269-17275.
Tabuchi A, Sakaya H, Kisukeda T, Fushiki H, and Tsuda M (2002) Involvement of an upstream stimulatory factor as well as cAMP-responsive element-binding protein in the activation of brain-derived neurotrophic factor gene promoter I. J Biol Chem 277: 35920-35931.
Takeuchi Y, Miyamoto E, and Fukunaga K (2002) Analysis on the promoter region of exon IV brain-derived neurotrophic factor in NG108 -15 cells. J Neurochem 83: 67-79.[CrossRef][Medline]
Tan J, Ruttiger L, Panford-Walsh R, Singer W, Schulze H, Kilian SB, Hadjab S, Zimmermann U, Kopschall I, Rohbock K, et al. (2007) Tinnitus behavior and hearing function correlate with the reciprocal expression patterns of BDNF and Arg3.1/arc in auditory neurons following acoustic trauma. Neuroscience 145: 715-726.[CrossRef][Medline]
Tao X, West AE, Chen WG, Corfas G, and Greenberg ME (2002) A calcium-responsive transcription factor, CaRF, that regulates neuronal activity-dependent expression of BDNF. Neuron 33: 383-395.[CrossRef][Medline]
Thoenen H (2000) Neurotrophins and activity-dependent plasticity. Prog Brain Res 128: 183-191.[Medline]
Timmusk T, Palm K, Metsis M, Reintam T, Paalme V, Saarma M, and Persson H (1993) Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10: 475-489.[CrossRef][Medline]
Vallet VS, Casado M, Henrion AA, Bucchini D, Raymondjean M, Kahn A, and Vaulont S (1998) Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. J Biol Chem 273: 20175-20179.
Vane JR, Bakhle YS, and Botting RM (1998) Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 38: 97-120.[CrossRef][Medline]
Waka N, Knipper M, and Engel J (2003) Localization of the calcium channel subunits Cav1.2 (alpha1C) and Cav2.3 (alpha1E) in the mouse organ of Corti. Histol Histopathol 18: 1115-1123.[Medline]
Wallhäusser-Franke E, Mahlke C, Oliva R, Braun S, Wenz G, and Langner G (2003) Expression of c-fos in auditory and non-auditory brain regions of the gerbil after manipulations that induce tinnitus. Exp Brain Res 153: 649-654.[CrossRef][Medline]
West AE, Chen WG, Dalva MB, Dolmetsch RE, Kornhauser JM, Shaywitz AJ, Takasu MA, Tao X, and Greenberg ME (2001) Calcium regulation of neuronal gene expression. Proc Natl Acad Sci U S A 98: 11024-11031.
Wiechers B, Gestwa G, Mack A, Carroll P, Zenner HP, and Knipper M (1999) A changing pattern of brain-derived neurotrophic factor expression correlates with the rearrangement of fibers during cochlear development of rats and mice. J Neurosci 19: 3033-3042.
Zafra F, Lindholm D, Castren E, Hartikka J, and Thoenen H (1992) Regulation of brain-derived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J Neurosci 12: 4793-4799.[Abstract]
Zha XM, Bishop JF, Hansen MR, Victoria L, Abbas PJ, Mouradian MM, and Green SH (2001) BDNF synthesis in spiral ganglion neurons is constitutive and CREB-dependent. Hear Res 156: 53-68.[CrossRef][Medline]
Zuccato C, Ciammola A, Rigamonti D, Leavitt BR, Goffredo D, Conti L, MacDonald ME, Friedlander RM, Silani V, Hayden MR, et al. (2001) Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293: 493-498.
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