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1Department of Neurobiology and Behavior, State University of New York, Stony Brook, New York; and 2Department of Physical Medicine and Rehabilitation, University of California, Irvine, California
Submitted 22 February 2005; accepted in final form 13 May 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). This makes it a potentially very useful molecule to promote recovery after spinal cord injury (SCI). However, BDNF has been shown to have other actions that might make its use after injury problematic. BDNF binds to the tyrosine kinase (trk) B receptor, which is present on neurons throughout the superficial dorsal horn (Bradbury et al. 1998). BDNF is expressed in small trkA-expressing sensory neurons and is upregulated in these neurons after peripheral inflammation induced by NGF or complete Freund's adjuvant (Apfel et al. 1996; Michael et al. 1997). Interference with the spinal action of BDNF has been shown to attenuate the pain produced by inflammatory mediators (Mannion et al. 1999; Pezet et al. 2002).
Recently we showed in neonatal rats (
P14) that BDNF produces long-lasting facilitation of synaptic responses elicited in substantia gelatinosa (SG; lamina II) by stimulation of dorsal roots, a process requiring the phospholipase C pathway and N-methyl-D-aspartate (NMDA) receptors located on the postsynaptic neuron (Garraway et al. 2003). The results of that study suggest that the ability of BDNF to produce LTP-like synaptic facilitation in lamina II neurons may underlie its spinal pronociceptive actions, a conclusion supported by the recent finding that it promotes phosphorylation of the NMDA receptor in the superficial dorsal horn (Slack et al. 2004). These recent findings along with the fact that pain is a common problem in spinal-cord-injured patients indicates that the use of BDNF to promote recovery after SCI requires careful evaluation of its effect on the nociceptive pathway under these conditions.
It is against this backdrop that we have undertaken an electrophysiological study to evaluate the effects of BDNF on the synaptic input to cells in lamina II in the contused spinal cord. Because much of our previous work had been carried out on slice preparations from the neonatal spinal cord (P14), we have investigated the effects of contusion injury carried out at P2 on the response of lamina II neurons. In the present study we have extended our findings to young adults both for uninjured cords as well as for cords contused at P2.
The facilitating effect of BDNF on dorsal-root-evoked AMPA/kainate receptor-mediated synaptic currents on spinal neurons, including those in lamina II, has been shown to require functional activity of NMDA receptors (Arvanian and Mendell 2001; Garraway et al. 2003). Therefore in the present studies we have also evaluated the functionality of the NMDA receptors in lamina II. This determination was very important in view of considerable immunocytochemical and physiological evidence that NMDA receptors in spinal neurons as well as in other regions of the brain become less functional during postnatal development (Arvanian et al. 2004; Barnes et al. 1997; Fitzgerald and Jennings 1999; Kalb et al. 1992; Potier et al. 2000).
Some of these results are published in abstract form (Garraway et al. 2004).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Spinal cord injury: contusion model
Two- or three-day-old (P2 or P3) pups were anesthetized by hypothermia induced by placing them on a bed of ice for 
10–12 min. All surgical procedures were carried out under aseptic conditions using betadyne and alcohol under a dissecting microscope. Pups received laminectomy at T12–T13 and were placed in a plastic tray with a wax mold to stabilize them for contusion. Cold anesthesia has the potential to exert a protective effect from spinal cord injury (SCI), and it is difficult to control the level of anesthesia induced by this method. The pups were aligned under the force probe to produce even bilateral bruising, but the contusion injury was not administered until immediately after the pup was observed to take its first spontaneous inhalation to ensure a uniform depth of anesthesia. Because spontaneous breaths are quite far apart at this stage of cold anesthesia, it was possible to initiate contusion injury in the interval between respiratory movements, thus minimizing the effect of vertical excursion of the spinal column even though animals this age could not be stabilized by clamping the vertebral column. Pups received 30 kilodyne contusion injuries using the Infinite Horizon (IH) Impactor (PSA) mouse force probe. They exhibited definite hindlimb paralysis immediately on recovery from anesthesia. Preliminary experiments varying time and recovery from cold anesthesia at different kilodyne force injury levels determined that this method produced the most reproducible observable bruising of the exposed spinal cord on examination under the dissecting microscope.
After contusion injury, pups were immediately transferred to a water jacketed heating pad maintained at 37°C, the skin was closed using monofilament nylon thread (Ethilon 7.0; Ethicon, Johnson and Johnson) sutures, and the animals were cleaned thoroughly by repeated swabbing with sesame oil to remove all odors associated with the surgical procedure. It was not possible to suture muscle layers in neonates, as the tissue was too fragile to hold the suture. On full recovery from anesthesia, usually 1 h after surgery, pups were returned to their dams. Maternal grooming was sufficient to maintain bladder expression post-SCI.
Electrophysiological recording (see following text) was performed on transverse spinal slices of L2–L5 segments which is adjacent to the injured area. Cords from individual animals were studied as early as 1 day and as late as 6 wk after the contusion.
Preparation of spinal cord slices and electrophysiology
The details of this experimental procedure are reported elsewhere (Garraway et al. 2003). Uninjured animals consisted of young rats (P14–P40). Results from previously published experiments carried out in the same laboratory with an identical protocol in slices from rats younger than P14 (Garraway et al. 2003) were used to evaluate age-related effects in slices from intact preparations. The animals were first anesthetized using halothane (<P10) or 10% urethan (
P10; 2g/kg body wt ip). Spinal segments L2–L5 were removed, embedded in Agar, 2.5% wt/vol, (type E, Sigma) and sliced on a motorized advance vibroslice (Campden Instruments) in 500-µm transverse sections. Short dorsal rootlets remained attached to the spinal segments to allow for electrical stimulation of primary afferents. Cooled high-sucrose-containing artificial cerebrospinal fluid (ACSF) containing (in mM) 259 sucrose, 2.5 KCl, 11 glucose, 1.25 NaH2PO4, and 26 NaHCO3 at a pH of 7.3 and oxygenated with 95% O2-5% CO2 was used. Slices were incubated at 32°C for 1 h in normal oxygenated ACSF containing (in mM) 125 NaCl, 2.5 KCl, 2 CaCl2, 1 MgCl2, 11 glucose, 1.25 NaH2PO4, and 26 NaHCO3 at a pH of 7.3, then transferred and affixed to a recording chamber that was continuously superfused with oxygenated normal ACSF at a flow rate of 1 ml/minute maintained at room temperature (20°C). The whole cell "blind" patch-clamp recording technique (Blanton et al. 1989) was carried out using the Axopatch 200B amplifier (Axon Instruments) filtered at 5 kHz (low-pass Bessel). Voltage- and current-clamp data were acquired using pCLAMP acquisition software (v 8.1; Axon Instruments). Patch electrodes were prepared from 1.5 mm OD capillary tubes (World Precision Instruments or A-M systems) pulled in a two-stage process (Narishige PC10) to produce resistance values ranging from 6 to 10 M
and filled with recording solution containing (in mM) 135 K-gluconate, 1 CaCl2, 2 MgCl2, 5 EGTA, 5 HEPES, 5 phosphocreatine, 4 Mg-ATP, 1 GTP, pH 7.3. QX-314 (2 mM) was added to the recording solution to block fast sodium currents. All chemicals for ACSF and intracellular solution were obtained from Sigma (St. Louis, MO).
Primary afferent stimulation
The attached dorsal roots were electrically stimulated using suction electrodes to evoke submaximal excitatory postsynaptic currents (EPSC) in the recorded SG neurons. To recruit C fibers, which terminate primarily in the SG, high-intensity stimulation (refer to Thompson et al. 1990) was used to evoke synaptic responses in these neurons, which were voltage clamped at –60mV.
Application of neurotrophin
After a baseline of evoked EPSCs collected at a low stimulus frequency (0.0167 Hz) for a period of 10 min, BDNF (generously provided by Regeneron Pharmaceuticals, Tarrytown, NY) was added to the superfusate at 200 ng/ml and applied for 20 min while maintaining the stimulation. BDNF was then washed out while synaptic currents were elicited for 20 min. In all studies described in this report, each slice was used for only a single application of BDNF or other drugs, and overall the number of cells (slices) used per pup averaged 1.7.
Glutamate receptors
To study NMDA receptor contribution to evoked synaptic responses and BDNF-induced modifications, two types of experiments were performed. First, to isolate synaptic NMDA current, a "cocktail" consisting of 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX, 10 µM; Sigma-RBI), bicuculline (5 µM, Tocris Labs, Ballwin, MO), CGP 35348 (10 µM, Ciba Geigy- Basel), and strychnine (5 µM, Sigma-RBI) was added to the superfusate to block the AMPA/ka, GABAA, GABAB, and glycine receptors, respectively. The resulting current could be blocked completely by application of the NMDA receptor blocker D-APV (40 µM; Sigma-RBI).
Second, 50 µM of NMDA was applied in the presence of 1.0 µM tetrodotoxin (TTX; Sigma-RBI: used to block all presynaptic input to the recorded SG neurons) for 1 min. This concentration of NMDA generally induced inward current in spinal neurons. To study the effect of BDNF on the NMDA-induced current, BDNF (in the presence of TTX) was applied for 20 min beginning after recovery from the initial NMDA-induced depolarization (usually 15–20 min), and this was followed by an identical NMDA application. This took place approximately 40 min after the first application of NMDA.
Analysis
Recordings were analyzed off-line using pCLAMP (v 8.1, Axon Instruments). The mean control value was calculated in response to stimulation before the test agents were applied. The mean percent change in synaptic amplitude after BDNF treatment was calculated as the difference between the mean peak amplitude during drug application (the first three traces after drug application were not included) and the mean value of the synaptic responses before drug (control) [% change = (DrugAvg – ControlAvg)/ControlAvg) x 100]. For the NMDA-induced current, the amplitude of the evoked current was measured as the difference between the maximum inward current induced after NMDA application and the baseline current just prior to NMDA application. Percent change for NMDA current was calculated from the difference between the amplitude of the current elicited by the first and second NMDA applications. Unless otherwise stated, all percent changes are reported as means ± SE. Comparisons were made using two-tailed t-test or paired t-test. When more than one cell in different slices from the same animal were studied to obtain a particular measure, e.g., the effect of BDNF on AMPA- or NMDA-evoked current, the results over all cells in that animal were averaged so that the number of observations used to evaluate the statistical tests was equal to the number of animals, not the number of cells.
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RESULTS |
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A total of 38 neurons were recorded from lamina II in slices taken from intact rats older than P14. Immediately after establishing the whole cell recording configuration at –80 mV, the mean membrane potential determined for these neurons was –62 ± 1.4 mV. The mean latency of the synaptic response averaged 2.6 ms, somewhat shorter than the 3.6 ms average latency for responses obtained from spinal slices taken from the younger rats (<P14). Because the conduction distance was about the same for both age groups, we assume that the difference is due largely to increased conduction velocity of the responsible afferent fibers in the older animals. The mean time to peak of the EPSC was very similar to that observed in younger animals (Garraway et al. 2003) (Fig. 1 A). As with cells from younger animals (Garraway et al. 2003), the responses of lamina II cells in these older preparations required high-intensity stimulation to the dorsal root, typically 300 µA, 500 µs, indicative of C fibers. The initial component of the EPSCs did not fluctuate in latency suggesting a monosynaptic input (Garraway et al. 2003) and were excitatory with an average amplitude of 105 ± 10 pA (n = 10), no different from EPSCs evoked in younger rats (118 ± 9 pA; n = 41; Fig. 1Ci).
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A total of 23 of the 38 lamina II neurons obtained from 10 animals older than P14 were tested with BDNF. BDNF produced significant synaptic facilitation (P < 0.01, paired t-test) averaging 25 ± 6% in these animals, which was not different (P > 0.05) from the significant facilitation (P < 0.01) of 29 ± 6% measured in 41 younger rats (Fig. 1Cii). This indicates that the ability of BDNF to potentiate dorsal root input in lamina II is maintained beyond P14. As in the younger rats, there was no apparent relationship between the amplitude of the untreated evoked AMPA current and the magnitude of the effect of BDNF. Also, as in the younger rats, the facilitation produced by BDNF was not reversed during the wash. Generally, preparations from the older rats exhibited a slower onset of facilitation during BDNF application (Fig. 1B, example of 1 cell).
NMDA receptor function
Six lamina II neurons from five rats older than P14 were tested by measuring the inward current elicited by exogenous NMDA applied in the presence of TTX. In these older rats, NMDA induced a peak current averaging 44 ± 14 pA compared with 106 ± 20 pA in six younger rats (Fig. 2A; P < 0.05). In three of these neurons, BDNF was applied for 20 min after the initial NMDA application, and this was followed by a second NMDA application. BDNF produced a modest facilitation of the NMDA response averaging 23% in these three neurons. Figure 2B shows an example of BDNF-induced facilitation of NMDA-evoked current in a neuron of an older animal.
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; Yoshimura and Jessell 1990). Because we observed a significant age-related decrease in the current elicited by bath applied NMDA, we wished to determine whether synaptic NMDA receptor function is also decreased. In nine neurons from older animals, we used either a "cocktail" of blockers to isolate any resulting NMDA receptor-mediated synaptic component (see METHODS) or we first added the NMDA receptor blocker D-APV to see if the longer-latency component of the EPSC was blocked. In four neurons studied with CNQX and the other blockers, the entire EPSC response was abolished (Fig. 3 A). In the remaining five neurons, where D-APV was first added, there was no change in the shape of the EPSC (Fig. 3B) in contrast to observations in cells from younger rats (Garraway et al. 2003). However, when CNQX was subsequently added, the response was completely blocked (not shown). These findings indicate that there is no contribution of NMDA receptors to the DR-evoked EPSC in these neurons unlike EPSCs evoked under similar conditions in SG neurons from preparations obtained from rats younger than P14 where 80% exhibited a D-APV- sensitive polysynaptic component (Garraway et al. 2003). Together, these findings indicate a decline in NMDA receptor function in lamina II after the first two postnatal weeks (also refer to Yoshimura and Nishi 1993).
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; Arvanian et al. 2004). Spinal cord contusion injury
Recordings were made from a total of 82 neurons (average resting membrane potential of –63 ± 1 mV) in slices from 42 rats contused at P2/3. No significant difference was observed overall in the amplitude of evoked AMPA/kainate current between cells taken from contused and uninjured rats (125 ± 11 pA, n = 24 for contusion vs. 115 ± 6 pA, n = 51 uninjured; P > 0.05) (Fig. 4 A). However, unlike neurons obtained from uninjured animals where BDNF significantly potentiated synaptic transmission (Garraway et al. 2003), bath application of BDNF did not produce any significant changes in EPSC amplitude in neurons from contused rats (–2 ± 5%, n = 24, P > 0.05; Fig. 4B). The effects of BDNF were virtually identical in both age groups. Furthermore, comparison of the effect of BDNF on the overall population of injured and uninjured neurons revealed a significant difference (P < 0.05; Fig. 4B).
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P14: 83 ± 25 pA, n = 6) was significantly (P < 0.05) larger than the average measured in cells from older rats (38 ± 5 pA, n = 11). Although BDNF was unable to facilitate the AMPA/kainate response after contusion, it could facilitate responses to NMDA in many neurons after contusion, but the effect was not significantly different from that observed in intact preparations (Fig. 4B). |
DISCUSSION |
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). A related possibility is the reduced access of BDNF to trkB receptors because of the increased presence of truncated trkB receptors also reported in the vicinity of a contusion injury (Liebl et al. 2001; also refer to King et al. 2000). Truncated receptors that are unable to drive intracellular signaling pathways might nonetheless "lure" BDNF into a nonproductive binding and in so doing prevent it from eliciting its normal effects (Houle and Ye 1999). Although we did not directly address this possibility in the present work, we did observe that BDNF could still elicit some spinal effects, specifically in facilitating the response to bath applied NMDA. This action of BDNF was somewhat reduced although the wide variability in the effects prevents us from reliably concluding whether these differences are statistically significant.
We also found changes in NMDA receptor responsiveness of lamina II neurons in these experiments. The most definitive change was associated with age. Older animals (>P14) exhibited significantly smaller NMDA responses than younger neonates (P14) both in intact and in preparations contused at P2 or P3. These observations are consistent with findings in other CNS regions that NMDA receptor-mediated responses are largest during the first postnatal week and decrease subsequently (e.g., Arvanian et al. 2004; Barnes et al. 1997; Potier et al. 2000). Contused preparations exhibited smaller NMDA responses than intact preparations, but these changes were not statistically significant.
Our previous work both in lamina II neurons (Garraway et al. 2003) and in motoneurons (Arvanian and Mendell 2001) has pointed to an important role for NMDA receptors in mediating the ability of BDNF to facilitate the synaptic AMPA/kainate receptor-mediated responses. The present data are not in conflict with this, but they suggest that the relationship between NMDA receptor function and the ability for BDNF to enhance AMPA/kainate receptor responses is highly non linear. Pharmacological inactivation of NMDA receptor responsiveness eliminated the ability of BDNF to potentiate the AMPA/kainate response (Garraway et al. 2003). In the present experiments, a significant decline short of complete abolition in NMDA responsiveness as the animal develops had no significant effect on BDNF-induced potentiation of the AMPA/kainate response.
The finding that contusion injury abolished the ability of BDNF to facilitate the AMPA/kainate receptor-mediated response of lamina II neurons despite no significant change in the NMDA responsiveness of these neurons suggests that changes in trkB expression are the more important determinant of the changes in BDNF effects reported here. The small decline in NMDA responsiveness was probably insufficient to account for these changes in BDNF action in view of the finding that the larger changes associated with maturation were unable to alter the effect of BDNF on AMPA/kainate receptor-mediated synaptic responses.
Other workers have investigated changes in AMPA and NMDA glutamate receptor expression in the contused spinal cord (Grossman et al. 1999, 2000). Unfortunately, it is difficult to connect these findings directly with ours because the changes in receptor expression were highly cell specific, and cells in the superficial dorsal horn were not studied. However, these changes appeared to be biased in favor of decreased receptor expression and the changes became more pronounced over the first weeks after contusion. Contusion in neonates (P14-15) resulted in a more substantial decrease in AMPA and NMDA receptor expression particularly within hours of contusion but the changes were largely reversed after 28 days (Brown et al. 2004). Our finding of moderately diminished glutamate receptor-mediated currents after contusion are qualitatively in agreement with a decrease in glutamate receptor expression but further experiments will be necessary to resolve whether other mechanisms might participate in determining these changes. Although not studied here, it will be necessary to incorporate recent findings (Mills et al. 2002) on the role of metabotropic glutamate receptors in the pain that accompanies spinal cord injury.
These studies also provide new information concerning the maturation of the DR input to cells of lamina II in uninjured preparations. There were no changes in the amplitude or latency of the synaptic AMPA currents or the resting membrane potential of these neurons. BDNF continued to facilitate the DR input in cells from the older animals despite a significant decrease in current elicited by bath-applied NMDA and the complete abolition of NMDA current in response to DR stimulation. In motoneurons, it is required that the NMDA receptors mediating the effects of BDNF be activated by the same synaptic input as that eliciting the AMPA/kainate receptor-mediated response facilitated by BDNF (Arvanian et al. 2004). Our findings in lamina II cells indicate that this requirement is relaxed suggesting different topography of synaptic interaction and/or intracellular signaling in these two cell types.
The observation that BDNF-induced facilitation of the AMPA/kainate receptor-mediated synaptic response was abolished after contusion injury was initially surprising given the widespread evidence of increased pain in patients after spinal cord injury (Bonica 1991; Mariano 1992; Siddall and Loeser 2001; Werhagen et al. 2004). However, unlike the situation after contusion, studies in models of chronic pain indicate an up-regulation of trkB in the spinal cord (Narita et al. 2000) and enhanced level of BDNF in the spinal cord and dorsal root ganglia (Cho et al. 1997; Fukuoka et al. 2001; Ha et al. 2001; Kerr et al. 1999; Miletic and Miletic 2002). Thus BDNF facilitation of responsiveness of cells in the lamina II is very likely not an important factor in the increased pain observed in spinal cord injured patients. Critically, one limitation in generalizing these findings is that the contusion injuries in these experiments were carried out in neonates. Because some of the systems involved in the response to contusion undergo maturation from neonate to adult, it is possible that different results would be obtained if similar experiments were carried out in animals injured as adults. This would provide valuable insights to understanding developmental factors influencing the regulation of circuits mediating nociceptive input after spinal cord injury.
The decline in BDNF function described here was also unexpected because there is now extensive evidence in adults suggesting that BDNF administered into the damaged region can improve motor function after spinal cord injury by increasing survival of injured neurons by acting as a promoter of axonal regeneration and/or by fostering reorganization of existing circuits by mechanisms such as sprouting (McTigue et al. 1998; Mocchetti and Wrathall 1995; Tobias et al. 2005). The persistence of BDNF's ability to promote neuronal survival and axonal elongation mechanism despite the precipitous decline in its ability to facilitate nociceptive inputs may reflect the requirement of the latter action of BDNF for functional NMDA receptors (Garraway et al. 2003) the function of which declines particularly at longer times (>2 wk) after the neonatal contusions studied here. We also cannot discount the possibility that trkB receptors involved in these functions are affected differently, related perhaps to neonatal injury versus adult injury, to proximity of the cell body of the trkB expressing cell to the contusion injury site, or to specific neuronal types involved. Perhaps most important is the conclusion that not all BDNF-mediated responses are affected in the same way after spinal cord injury.
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ACKNOWLEDGMENTS |
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Present address of S. M. Garraway: Dept of Pharmacology, Weill Medical College, Cornell University, New York, NY 10021.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. M. Mendell, Department of Neurobiology and Behavior, 550 Life Sciences Bldg., State University of New York, Stony Brook NY 11794-5230 (E-mail lorne.mendell{at}sunysb.edu)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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