DREAM regulates BDNF-dependent spinal sensitization
- Ivan Rivera-Arconada†1,
- Tomaso Benedet†2, 3,
- Carolina Roza1,
- Begoña Torres2, 3,
- Jorge Barrio2,
- Agnieszka Krzyzanowska4,
- Carlos Avendaño4,
- Britt Mellström2, 3,
- José A Lopez-Garcia1Email author and
- José R Naranjo2, 3Email author
© Rivera-Arconada et al; licensee BioMed Central Ltd. 2010
Received: 23 September 2010
Accepted: 18 December 2010
Published: 18 December 2010
The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca2+- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia.
L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents. Peripheral inflammation produced enhancement of spinal reflexes and increased expression of BDNF in wild type but not in DREAM transgenic mice. The enhancement of the spinal reflexes was reproduced in vitro by persistent electrical stimulation of C-fibers in wild type but not in transgenic mice. Exposure to exogenous BDNF produced a long-term enhancement of dorsal root-ventral root responses in transgenic mice.
Our results indicate that endogenous BDNF is involved in spinal sensitization following inflammation and that blockade of BDNF induction in DREAM transgenic mice underlies the failure to develop spinal sensitization.
Transcriptional repressor activity of DREAM depends on their high affinity Ca2+- dependent binding as a heterotetramer to DRE (downstream regulatory element) sites in target genes [1–4]. Increased levels of intracellular Ca2+ result in DREAM unbinding from DNA and transcriptional derepression . Binding to DRE sites is controlled also by the interaction with other nucleoproteins [5, 6]. DREAM mutants unable to respond to Ca2+, cAMP and/or to establish protein-protein interactions, function as cross-dominant constitutively active mutants (daDREAM) and repress permanently target genes in vivo [7, 8]. Several genes have been shown to be regulated by DREAM, including prodynorphin, c-fos , AA-NAT, ICER , and BDNF  NCX-3  and several cytokines in T lymphocytes . DREAM, also known as calsenilin or KChIP-3 (K+ channel interacting protein 3), interacts with presenilins or Kv4 potassium channels, respectively [10, 11].
Genetic ablation of DREAM in DREAM-/- mice results in increased thresholds for noxious stimuli that have been associated to increased prodynorphin gene expression and to reduction in A-type currents (IA) in spinal cord neurons [12–14]. However, reduction of A-type currents in spinal cord neurons of Kv4.2 deficient mice are associated with thermal and mechanical hyperalgesia and reduced responses to inflammation .
BDNF is implicated in the maintenance of peripheral sensory neurons during development and in the regulation of synaptic plasticity and long-term potentiation in the adult brain and spinal cord [16–19]. Expression of the BDNF gene depends on several regulatory regions . Activity-dependent BDNF induction, following pain stimulation, is mainly controlled by regulatory elements in exon III in the rat gene. This includes, a hemi-palindromic CRE site that mediates CaMK IV-dependent transactivation by CREB/CBP following neuronal depolarization [21, 22], two Ca2+-responsive elements, the CaRE sites, that bind the calcium responsive factor (CaRF)  and a DRE site that binds the transcriptional repressor DREAM .
Here we used transgenic mice expressing a cross-dominant constitutively active DREAM mutant to further analyze the functional role of DREAM in pain transmission and sensitization. Behavioral studies revealed that DREAM transgenic mice possess high sensitivity to thermal and chemical noxious stimuli and reduced hyperalgesic response to inflammation. Electrophysiological studies performed in isolated spinal cord of DREAM transgenic mice indicate the absence of hyperreflexia, a sign of sensitization , in response to persistent activation of nociceptive afferents. Quantitative real time-PCR showed that basal and inducible expression of BDNF is reduced in spinal cord and dorsal root ganglia (DRG) from DREAM transgenic mice. Though expression of the constitutively active DREAM mutant might affect the expression of several downstream genes, BDNF supplementation is enough to restore the capability of the spinal cord of DREAM transgenic mice to develop hyperreflexia.
Characterization of L1 daDREAM transegenic mice
Basal hyperalgesia and delayed sensitization to noxious stimuli in daDREAM transgenic mice
Increased spinal reflexes in daDREAM mice
A-type currents in spinal cord neurons from L1 mice are normal
A-type currents have been associated with neuronal plasticity in the hippocampus  and the spinal cord . The Ca2+-insensitive DREAM/KChIP3 mutant has been previously shown to affect gating of Kv4 potassium channels in vitro  and a weak change in A-type currents has been reported in DREAM deficient neurons . We investigated whether a change in A-type currents in dorsal horn neurons from L1 mice could contribute to the basal hyperalgesia observed in daDREAM mice.
Basic electrophysiological properties (current-clamp) and major traits for transient (IA) currents (voltage-clamp) of neurons from wild type and transgenic mice
Number of neurons
-55.7 ± 0.8f
-53.9 ± 1.2
355 ± 20
387 ± 57
65 ± 2
68 ± 3
-39.7 ± 0.7
-40.1 ± 1.3
Number of neurons
Max current density (pA/pF)
15.3 ± 3.3
14.5 ± 8.4
Time constant (ms)
15.9 ± 1.5
15.7 ± 2.8
Activation; V50 e (mV)
-22.5 ± 2.1
-20.1 ± 2.6
Activation; slope factor
8.4 ± 0.7
6.5 ± 0.7
Inactivation; V50 e (mV)
-43.9 ± 1.7
-40.1 ± 2.5
Inactivation; slope factor
-10.5 ± 1.0
-9.5 ± 0.9
Lack of spinal sensitization in L1 mice following inflammation and low frequency stimulation of C-fibres
BDNF mediates long-term enhancement of DR-VRRs
BDNF is believed to play an important role in spinal plasticity and sensitization following carrageenan-inflammation . Therefore, we investigated whether reduced spinal levels of BDNF could be responsible for the lack of central sensitization observed in transgenic mice.
We then analyzed changes in DR-VRRs before and after exogenous applications of BDNF to spinal cords of wild type and L1 mice. Consistent with our previous result that TrkB receptor mRNA levels are not modified in L1 mice, the response to exogenous addition of BDNF was similar in spinal cords from wild type and L1 mice (Figure 8B, C). In both cases, BDNF superfusion produced a significant 2-fold increase in spikes associated to the DR-VRRs elicited by a wide range of stimulus intensities involving activation of A- and C-fibres.
These results indicate that BDNF is essential for the development of spinal sensitization and suggest that sensitization would occur in L1 mice if they could mobilize enough BDNF in response to persistent activation of nociceptive afferents i.e. chronic inflammation or in response to injury. To test this hypothesis we analyzed the expression of BDNF mRNA in DRG and BDNF protein in spinal cord following the application of CFA. Importantly, the inflammatory response in wild type mice developed with an increase in BDNF mRNA levels that was maximal at 3 days and remained elevated 5 days after CFA injection (Figure 8D). In DRG from L1 mice, however, levels of BDNF mRNA were not increased at any time after CFA injection (Figure 8D). Importantly, western blot analysis of BDNF protein levels in spinal cord confirmed the mRNA data and showed a 70% decrease in BDNF protein levels in transgenic spinal cord and the absence of induction upon inflammation (Figure 8E). Conversely, a substantial increase in BDNF protein was readily observed in wild type mice upon inflammation (Figure 8E).
The dominant active mutant, daDREAM, blocks the regulated activity of endogenous DREAM/KChIP proteins when transgenic to endogenous mRNA ratio is as low as 1 to 6 . In this study, we show that in L1 transgenic mice the ratio daDREAM/DREAM mRNA is 1.6 to 1 and 1 to 3 in spinal cord and DRG, respectively, indicating that the expression of the dominant active mutant protein is sufficient to block Ca2+- and cAMP-mediated derepression by endogenous DREAM/KChIP proteins. As a result, expression of prodynorphin and BDNF, two potential targets for transrepression by DREAM that are related to pain, are reduced in DRG and spinal cord from L1 transgenic mice. Since the mutation at the LCD domain in daDREAM prevents its interaction with CREB , downregulation of prodynorphin and BDNF in L1 mice is not related to interference with CREB-dependent transcription and is due to direct repression by daDREAM. Importantly, changes in nociception are related to the expression of the transgene in spinal cord and DRG neurons, since sensory thresholds were normal in L26 mice in which daDREAM expression is confined exclusively to telencephalic areas. In the same way, another line of daDREAM mice, L33, without transgene expression in spinal cord and DRG neurons, did not show any change in pain sensitivity to thermal stimulation .
Previous work with DREAM-/- mice  demonstrated the involvement of this transcriptional repressor in pain modulation. Mice lacking DREAM showed a basal state of analgesia and reduced response to inflammatory and neuropathic treatments, that was interpreted as caused by elevated spinal cord levels of dynorphin A peptide observed in these mice . Consistent with this, the reduced expression of prodynorphin in L1 mice could account for the basal state of hyperalgesia found in adult mice. The basal hyperalgesia was paralleled by increased hyperreflexia in the isolated spinal cord without signs of change in the function of sensory afferents, suggesting that the exaggerated sensitivity is related to changes in spinal processing of afferent signals.
Activation of NMDA receptors plays a central role in the transmission of primary sensory information in the spinal cord [reviewed in ]. Recently, it has been shown that DREAM reduces the amplitude of NMDA currents in hippocampal neurons through a Ca2+-sensitive interaction between DREAM and PSD95  or between DREAM and the NR1 subunit of the receptor . On the other hand, it was previously shown that release of dynorphin peptides from presynaptic terminals inhibits glutamatergic trasmission through NMDA receptors . The increased hyperreflexia in isolated spinal cord and the increased basal sensitivity to pain stimulation suggest that a potential reduction in NMDA currents in spinal cord neurons in daDREAM transgenic mice is compensated by the reduced inhibition due to the low expression of prodynorphin.
In addition to the hypothesis of prodynorphin involvement, there is a convergence of data suggesting that transient A-type potassium currents, mediated by Kv4 channels, are responsible for hypersensitivity to acute pain stimuli. Genetic elimination of Kv4.2 reduces A-type currents and increases excitability of dorsal horn neurons, resulting in enhanced sensitivity to noxious stimuli , that resembles the scenario in L1 mice. Moreover, genetic ablation of Kv channels results in decreased expression of DREAM/KChIP proteins , suggesting a genetic auto-regulatory loop between these two gene families. Our results, however, are not consistent with the hypothesis that reduced expression of Kv channels in the spinal cord or malfunction of the associated currents, are responsible for the altered noxious sensitivity in L1 transgenic mice. On the contrary, we found small but significant increase in Kv4.2 and Kv4.3 mRNA levels in the spinal cord and, more important, we found that IA currents in dorsal horn neurons from L1 mice were indistinguishable from those of wild type mice in terms of various properties, including current density and kinetics.
Reduced prodynorphin levels may explain basal hypersensitivity of L1 mice, however, does not account for the reduced behavioral response to inflammation following CFA injection. Importantly, isolated transgenic spinal cords were not capable to show signs of central sensitization, which may be causal for the anomalous response to inflammatory stimuli. Whereas spinal cords from carrageenan-treated wild type mice showed a marked hyperreflexia, L1 mice with or without treatment, showed essentially similar spinal reflexes. Furthermore, persistent low frequency stimulation of primary C-afferents caused a long-term enhancement of DR-VRRs in wild type but not in L1 mice. It is worth noting, that similar protocols of stimulation  have been shown to produce LTP in superficial laminae neurons in a process that resembles central sensitization induced by inflammation.
In order to understand how L1 mice fail to produce a normal process of central sensitization, we considered the reduced expression levels of BDNF in L1 mice. Reduced BDNF levels in vivo confirm previous in vitro studies showing the regulatory effect of DREAM on BDNF promoter activity . Several lines of evidence relate BDNF with central sensitization; i) intrathecal administration of exogenous BDNF produces hyperalgesia in wild type mice, whereas administration of antiserum directed against either BDNF or TrkB receptors prevent inflammation-induced hyperalgesia [29, 36], ii) conditional BDNF knockout mice do not develop hyperalgesia after inflammatory stimuli  and iii) at the functional level, BDNF has been shown to be required for simple forms of spinal reflex plasticity like wind-up  and to enhance the spinal response to sensory inputs [16, 39] through post-synaptic NMDA receptors  or by reversing chloride gradients in central afferent terminals . Here we show that BDNF is required also for longer lasting forms of plasticity in spinal reflexes. BDNF-/- mice did not develop long-term enhancement of ventral root reflexes following low frequency stimulation of C-fibers. Interestingly, BDNF-/+ mice were able to develop a small amplitude enhancement of reflexes, suggesting that the quantitative expression of BDNF in the spinal cord is correlated with the ability to develop long-term forms of spinal plasticity.
DREAM transgenic mice express normal levels of TrkB receptors in the spinal cord and therefore we were able to test the effects of exogenous applications of BDNF to the isolated spinal cord. BDNF produced a similar enhancement of spinal responses to afferent inputs in spinal cords from wild type and L1 mice, suggesting that the spinal cord from L1 mice does not receive enough BDNF from primary afferents after low frequency stimulation of C-fibers or after inflammation. The absence of induction in BDNF expression in dorsal root ganglia from L1 mice following inflammation supports this idea.
Transgenic L1 mice show a state of basal hyperalgesia most likely sustained by low spinal cord levels of dynorphin and which is not related to anomalies in Kv expression or function. More importantly, our work suggests that the reduced hyperalgesic response in L1 mice following peripheral inflammation and the reduced central sensitization is mostly due to deficient BDNF input in the spinal cord from primary afferents.
Animals and behavioral analysis
Experiments were performed with C57B/6×CBA mice. BDNF-/- mice were kindly provided by Dr. J. Alberch (University of Barcelona). The generation of DREAM transgenic mice has been described . Experiments were performed in adult male mice, homozygous for the transgene (line L1) and in wild type mice. Mice were housed five per cage in a temperature (21 ± 1°C) and humidity (65 ± 10%) controlled room with a 12-/12- h light/dark cycle (lights on from 8 am to 8 pm hours) with food and water ad libitum. Experiments took place during the light phase. Behavioral tests and animal care were conducted in accordance with the standard ethical guidelines (European Communities Directive 86/609 EEC; National Institutes of Health 1995) and approved by the local ethical committee (CNB-UAH). All experiments were carried out in blind conditions. Behavioral testing by plantar test, tail flick, writhing test and von Frey hairs were performed as described [24, 40–42]. Inflammation was induced by unilateral intraplantar injection of carrageenan (30 mg/ml in saline; 20 μl injection volume) or complete Freund adjuvant (50 μl) in P6-10 or adult mice.
RNA extraction and quantitative PCR
RNA from wild type and L1 spinal cord and dorsal root ganglia was prepared using TRIzol (Invitrogen) and the RNAeasy Mini Kit (Qiagen). RNA was quantified and the quality was assessed with a 2100 Bioanalyzer (Agilent). Quantitative real-time PCR for endogenous DREAM and mutant daDREAM was performed using a pair of primers able to amplify both: forward 5'-CACCTATGCACACTTCCTCTTC A-3' and reverse 5'-ACCACAAAGTCCTCAAAGTGGAT-3' and two TaqMan MGB probes; FAM-5'-TGCCTTCGATGCTGAT-3'-MGB and VIC-5'-CGCCTTTGCTGCGGC-3'-MGB, specific for DREAM and daDREAM, respectively. The results were normalized by quantification of HPRT mRNA using the specific primers; forward 5'-TTGGATACAGGCC AGACTTTGTT-3' and reverse 5'-CTGAAGTACTCATTATAGTCAAGGGCATA-3', and the probe FAM-5'-TTGAAATTCCAGACAAGTTT-3'-MGB. Quantitative PCR for prodynorphin, BDNF and TrkB were performed using kits from Applied Biosystems.
Western blot analysis
Lumbar segments (L4 and L5) were dissected, frozen at -70°C and homogenized in extraction buffer [100 mM PIPES, pH 7.0; 0.5 M NaCl; 0.2% Triton-X 100; 2% BSA; 2 mM EDTA; protease inhibitors Complete Mini (Roche)]. After centrifugation at 16,000× g for 30 min, spinal cord extracts were resolved in SDS-PAGE and transferred to PVDF membranes (Millipore). Antibodies against β-actin (clone AC-15, Sigma) and BDNF (affinity purified sheep anti-BDNF, OSB00026A, Osense) were used and blots were developed using ECL (Supersignal West Dure, Pierce). Band intensity were quantified using the software QuantityOne (Biorad) and related to β-actin to correct for protein loading.
In vitro spinal cord preparation and dorsal root stimulation
Wild type and transgenic (L1) 6-11 days-old mice of either sex weighing between 4.3 and 9.7 g were anaesthetized with urethane (2 g/Kg i.p.) and spinal cords were extracted following a rostrocaudal laminectomy . Entire or hemisected spinal cords (for ventral root or single cell recordings) were pinned down to a Sylgard-based recording chamber and maintained with oxygenated artificial cerebrospinal fluid (ACSF) at room temperature (22 ± 1°C). The composition of the ACSF was: (in mM) NaCl 127, KCl 1.9, KH2PO4 1.5, MgSO4 1.3, CaCl2 2, NaHCO3 22, glucose 10, (pH 7.4). One lumbar dorsal root (L4-L5) was placed in a tight fitting glass suction electrode and electrically stimulated to activate afferent fibers. Single stimuli of 200 ms duration were applied at a range of intensities to activate A-fibers or all fibers in the dorsal root . Wind-up stimuli consisted of 20 C-fiber intensity shocks (200 μs, 200 μA) applied at 1 Hz. Conditioning stimuli to produce a long-lasting enhancement of dorsal root-ventral root reflexes (DR-VRRs) consisted of 240 C-fiber intensity shocks (200 μs, 200 μA) delivered at 2 Hz.
Ventral root recordings
L4-L5 ventral roots were placed in a suction electrode to record averaged activity from motoneurons. Recordings were made with a Cyberamp (Axon Instruments, CA, USA) in AC mode as previously described . AC recordings showed individual fast events, or spikes or groups of spikes, reflecting the simultaneous firing of action potentials in a group of motoneurons. The number of such events was quantified using amplitude criteria as previously described . Responses to single stimuli were quantified as the number of spikes counted in a time window between 20 ms and 4 s from the stimulus artifact. Responses to trains of stimuli were quantified as the number of spikes within 20 ms and 0.95 s after each stimulus artifact of the train.
Current and voltage clamp recordings
Electrodes were pulled from borosilicate glass tubing with internal filament using a horizontal puller (Sutter instruments, Novato, CA, USA) giving resistances within the range of 6-9 MΩ. Internal solution consisted of: (in mM) KCl 30, EGTA 3, HEPES 40, MgCl2 2, potassium acetate 95, CaCl2 0.5, Na2-ATP 3, Na-GTP 0.3 (pH 7.4). Signals were amplified with a MultiClamp 700A amplifier (Axon Instruments, CA, USA) and analyzed offline with Spike 2 and Signal software (CED, Cambridge Electronic Designs, Cambridge, UK). Electrode tracking as well as current and voltage recordings were performed using protocols and procedures explained in full elsewhere . Transient potassium currents sensitive to 4-aminopyridine and insensitive to tetraethyl ammonium were isolated in the presence of 0.5 μM tetrodotoxin to block sodium currents and 100 μM cadmium chloride to block calcium and calcium-activated potassium currents as previously described [46, 47].
Drugs and chemicals
Carrageenan lambda, Complete Freund Adjuvant (CFA), cadmium chloride (CdCl2), tetraethyl ammonium (TEA), 4-aminopyridine (4-AP) and the components for the ACSF and the intracellular solution were from Sigma-Aldrich (Spain). Tetrodotoxin (TTX) was from Tocris Bioscience (Bristol, UK) and BDNF from Peprotech (CA, USA).
Statistical analysis and curve fittings were performed using Prism 4.0 (GraphPad Software, USA). Differences between pairs of mean values were analyzed using the Mann-Whitney test or One-way ANOVA. Responses to dorsal root stimulation and intracellular pulses were quantified in terms of number of spikes against intensity of dorsal root stimulus or intracellular pulse respectively, and the resulting curves were analyzed using Two-way ANOVA. Data of normalized conductance, activation and inactivation curves were treated as previously reported . Curves were compared by Two-way ANOVA followed by Bonferroni post-tests. Data is expressed as mean ± SEM, unless otherwise stated.
The work was supported by grants from Madrid Community (S-SAL-0305-2006) and the Spanish Ministry of Science and Innovation (CIBERNED, SAF2007-62449, SAF2008-03469 and SAF2009-07876) to (JRN, JAL, CA and BM).
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