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Department of Neurophysiology, Ruhr-University Bochum, D-44780 Bochum, Germany

	Abstract

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There is emerging evidence that injury of the cerebral cortex is followed by processes of enhanced neuroplasticity. In the present study, we investigate the functional properties of NMDA receptors (NMDARs) in the surround of focal lesions with recordings of extracellular field potentials (FPs) in acute slices of rat visual cortex at survival times of 2–6 days. FPs were recorded in cortical layer III lateral to the lesion, while long-term potentiation (LTP) was induced by theta-burst stimulation (TBS) in layer IV. The predominantly AMPA receptor-mediated FPs displayed a significantly enhanced LTP in the surround of the lesion at distances of 2–3.2 mm. The LTP was completely blocked by the NMDAR antagonist D-AP5. Ifenprodil, an antagonist of NMDARs containing the NR2B subunit, only slightly affected the LTP in slices from sham-operated animals, but significantly reduced the LTP in slices from lesioned rats. We quantitatively analysed the proportion of NMDARs containing the NR2B subunit after lesions by applying ifenprodil to pharmacologically isolated NMDAR-FPs. The NR2B antagonist reduced the NMDAR-FPs significantly more strongly at distances of 2.0–3.2 mm from the border of the lesion. This indicates that the early phase of increased synaptic long-term plasticity in the surround of cortical lesions is accompanied by an up-regulation of NMDARs containing the NR2B subunit.

(Received 7 June 2004; accepted after revision 22 July 2004; first published online 29 July 2004)
Corresponding author T. Mittmann: Department of Neurophysiology, MA 4/149, Ruhr-University Bochum, D-44780 Bochum, Germany. Email: mittmann{at}neurop.ruhr-uni-bochum.de

	Introduction

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Recent reports describe several processes of functional reorganization in the injured central nervous system which can partly compensate for the functional loss caused by cell death (Taub et al. 2002). Increased neuroplasticity following injury has been observed in the somatosensory (Jenkins & Merzenich, 1987) and visual systems in vivo (Eysel & Schweigart, 1999), and in vitro (Mittmann & Eysel, 2001). In general, the susceptibility of LTP is complex, because it depends on a number of overlapping processes that are recruited by different patterns of synaptic activity (Zakharenko et al. 2003). Under physiological conditions neocortical LTP primarily depends on the strength of the GABAergic inhibition and on the excitatory synaptic transmission mediated by ionotropic glutamate receptors of the NMDA (NMDAR) type (Artola & Singer, 1987; Yoshimura et al. 2003). Activation of NMDARs leads to calcium influx, which is one key trigger for the induction of LTP (Malenka et al. 1989). The NMDARs are heteromers consisting of NR1 subunits and one or more of four NR2 subunits (NR2A–D) (Monyer et al. 1994). The specific subunit composition determines the biophysical properties of the receptor, and can account for the magnitude of LTP (Quinlan et al. 1999). On the one hand, the longer excitatory postsynaptic current duration of NMDARs containing the NR2B subunit is accompanied by an increased postsynaptic Ca²⁺ influx and an enhanced LTP (Carmignoto & Vicini, 1992). On the other hand, the different intracellular C-termini of the NR2 subunits can trigger synaptic plasticity by serving as a critical scaffold for a complex intracellular signal transduction cascade (Sprengel et al. 1998). In fact, the susceptibility of LTP in young animals during the critical period correlates with the number of NMDARs containing the NR2B subunit (Barth & Malenka, 2001). In the present study we investigate the possible contribution of NMDARs containing the NR2B subunit to the enhanced LTP observed in the vicinity of lesions in the visual cortex.

	Methods

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In vivo lesions

Treatment of all animals was in accordance with the German regulations for experiments with vertebrate animals, and local ethics committee approval was obtained from the regional government for the experimental protocols.

Wistar rats (n= 37, age: 21–25 days) were anaesthetized by intraperitoneal injection of chloral hydrate (4%; 0.1 ml per 10 g). Small, focal laser lesions were induced as described previously (Mittmann & Eysel, 2001). The scull was exposed and cautiously thinned by drilling above the visual cortex without touching the dura mater. Multiple, partially overlapping round lesions were made through the translucent wet bone under visual control with a 810 nm infrared diode laser (OcuLight Slx, Iris Medical, USA) attached to a binocular operating microscope to form an elongated lesion of 1 mm mediolateral width and 4 mm anteroposterior length, 1 mm lateral to and parallel to the midline, starting anterior of the lambda suture in the visual cortex. Sham-operated littermates of the same age (n= 17) served as controls.

Electrophysiology

In vitro recordings were performed 2–6 days after surgery, a period in which enhanced synaptic plasticity was observed at the border of the lesions (Barmashenko et al. 2001; Mittmann & Eysel, 2001). Animals were deeply anaesthetized with ether and decapitated. Four to five coronal slices of 350 µm thickness containing the visual cortex were prepared using a vibratome (Leica, VT 1000 S, Germany). The slices were incubated in artificial cerebrospinal fluid (ACSF) containing (mM): 125 NaCl, 2.5 KCl, 1.25 NaH₂PO₄, 25 NaHCO₃, 25 D-glucose, 2 CaCl₂, 1.5 MgCl₂ and 1 µM glycine, bubbled with 95% O₂ and 5% CO₂ to pH 7.4. The cortical tissue recovered at room temperature at least for 1 h before individual slices were transferred to a submerged recording chamber, which was superfused with oxygenated ACSF at 32 ± 2°C. The recording chamber was mounted on the stage of an upright microscope (Olympus BX50-WI, Olympus, Japan) equipped with a 2.5 x objective (N.A. = 0.075; Zeiss).

A concentric bipolar stimulation electrode was placed in layer IV of the visual cortex to stimulate afferent fibres projecting to layer III either 0.7–1.9 mm or 2.0–3.2 mm lateral to the border of the lesion (Fig. 1A). The specific positions for stimulation were selected, since we have recently shown by use of intracellular recordings in the same animal model that an increase of synaptic plasticity was most prominent at distances of 2–4 mm from the border of the lesion (Mittmann & Eysel, 2001). Accordingly, the control FPs were acquired from sham-operated rats mainly in cortical area 18a corresponding to a lateral distance of 2.0–3.2 mm from the border of a lesion. Monophasic current pulses of 100 µs duration and intensities of 100–200 µA were used for electrical stimulation. Field potentials (FPs) were recorded with electrodes pulled from borosilicate glass capillaries (GB 150F-8P, Science Products, Germany), filled with standard ACSF (resistances 1–3 M). The FPs were amplified and low-pass filtered at 3 kHz using a differential amplifier (EPMS07, NPI Electronic, Germany). Traces were sampled at 50 kHz and analysed off-line using Clampex 6 (Axon Instruments, USA) and Spike2 (CED, UK) software.

View larger version (79K): [in this window] [in a new window]   Figure 1.  Extracellular field potential (FP) recordings in slices of the visual cortex post lesion A, photomontage from one hemisphere of a Nissl-stained slice from a 26-day-old rat 3 days post-lesion. Note the stimulation electrode in cortical layer IV, the recording electrode in layer III. The area inside the dotted rectangle is shown at higher magnification in B. B, the necrotic lesion centre is surrounded by a thin layer of < 200 µm containing partially damaged cells followed by histologically normal tissue. FPs were recorded at > 700 µm from the border of the lesion. C, representative extracellular recorded field potential (FP) recorded in layer III (continuous line) that is blocked by 10 µM DNQX (dashed line). The residual negativity is non-synaptic. The latency of the FPs is > 4.5 ms. D, a pharmacologically isolated NMDAR-FP (top traces, continuous line), which was blocked by 25 µM D-AP5 (top traces, dashed line). The remaining non-synaptic component was unaffected by D-AP5, but was blocked by 1 µM TTX (bottom trace).

The input–output relation of the FPs was measured after determining the stimulus intensity at 200 µs pulse duration that evoked the maximal FP amplitude. This stimulus intensity was kept constant while the stimulus duration was tested every 30 s in steps of 20 µs in the range between 40 and 200 µs.

For LTP experiments the stimulus intensity was adjusted to 40–60% of the maximal response amplitude and was kept constant over the entire recording period. The slices were stimulated with single test pulses every 30 s for at least 30 min, followed by theta-burst stimulation (TBS) and 60 min of test stimulation. Each TBS consisted of three synaptic trains (at 0.1 Hz) of 10 bursts (at 5 Hz) each providing four stimuli at 100 Hz with 200 µs stimulus duration. D-AP5 (Tocris, Biotrend) or ifenprodil (Sigma, Taufkirchen, Germany) were pre-incubated for at least 90 min. The time course of changes in the FP amplitudes was calculated in relation to the signals obtained during the last 10 min prior to TBS (100%), normalizing all responses to this baseline and then averaging across experiments. All changes in long-term synaptic plasticity were evaluated by averaging the 10 responses at 51–60 min post-TBS and comparing these data to the 10 control signals during the last 10 min prior to TBS. Representative example traces in the figures are averages of 10 consecutive voltage traces.

NMDAR-mediated field potentials were pharmacologically isolated in artificial cerebrospinal fluid (ACSF) containing 3 mM CaCl₂, 0.1 mM MgCl₂, 10 µM DNQX and 1 µM glycine (Fig. 1D, upper continuous line). These NMDA receptor-dominated FPs were evoked every 60 s. The NMDARs containing the NR2B subunit were blocked with the specific antagonist ifenprodil (3 µM). The remaining FP component was blocked by 25 µM D-AP5 (Fig. 1D, upper dotted line). The residual D-AP5 insensitive negativity was non-synaptic, TTX sensitive and independent of the lesion-induced changes (Fig. 1D, bottom trace). The ifenprodil-sensitive component of NMDAR-FPs was determined by use of pCLAMP9 software (Axon Instruments), which calculated the integral of each FP signal excluding the initial non-synaptic component (see Fig. 1D).

All data are presented as means ±S.E.M. Student's t and Mann-Whitney U tests were performed for statistical evaluation of the data.

	Results

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The extracellular FPs acquired in cortical layer III of sham-operated rat slices bathed in normal ACSF revealed a mean stimulus-to-peak latency of 5.6 ± 0.2 ms (n= 7). FPs measured in rats post-lesion at distances of 0.7–1.9 mm and at 2.0–3.2 mm from the border of the injury were not different in shape (Fig. 2A, 1 and 2) and stimulus-to-peak latency (lesion 0.7–1.9 mm: 5.3 ± 0.3 ms, n= 6, P= 0.53; lesion 2.0–3.2 mm: 5.0 ± 0.3 ms, n= 6, P= 0.1). In order to disclose lesion-induced changes in the basal excitability of the cortical network we measured the input–output relation of the FP responses in slices from sham-operated (n= 9) and from lesion-treated slices (n= 6). As shown by the example traces and by the summary graph in Fig. 2, the resulting signal amplitudes were not different (P > 0.05) over the entire range of stimulus durations from 40 µs to 200 µs.

View larger version (18K): [in this window] [in a new window]   Figure 2.  The basal synaptic transmission is not altered in the visual cortex postlesion A, representative examples of FPs with gradually increasing stimulus durations of 40 µs, 100 µs and 200 µs (1–3), respectively. B, the input–output curves present mean FP amplitudes with a constant stimulus intensity and gradually increasing stimulus durations in control slices () and in tissue of lesion treated rats at distances of 2.0–3.2 mm from the border of the lesion (•).

View larger version (39K): [in this window] [in a new window]   Figure 3.  LTP is increased at the border of the injury A, average voltage traces of FPs recorded in slices of a sham-operated rat (top voltage traces) and of a rat post-lesion (bottom voltage traces). Left traces (1) are averaged from the last 10 min prior to theta-burst stimulation (TBS); the right traces (2) were acquired at 51–60 min after TBS. The summary diagram shows the time course of changes in relative FP amplitudes following TBS in controls () and in lesion-treated rats at distances of 2.0–3.2 mm from the border of the lesion (•). B, expression of LTP is dependent on activity of NMDA receptors. Average voltage traces of AMPAR-FPs during LTP experiments performed in the presence of D-AP5 (25 µM) from one control slice (top traces) and from a slice at a distance of 2.7 mm from the border of the lesion (bottom traces). The summary diagram on the right shows the time course of the mean FP amplitudes recorded from control rats () and from lesioned rats at distances of 2.0–3.2 mm () in the presence of D-AP5.

Since it is known that NMDARs containing the NR2B receptor subunit are associated with enhanced synaptic plasticity (Tang et al. 1999), we repeated the LTP experiments in the presence of ifenprodil, a specific antagonist of NMDARs containing the NR2B subunit (Williams et al. 1993). Similar to the effect of D-AP5, bath application of ifenprodil did not change the stimulus-to-peak latency of the baseline FPs (sham-operated: stimulus-to-peak latency: 5.4 ± 0.2 ms; post-lesion d= 2.0–3.2 mm: stimulus-to-peak latency: 5.6 ± 0.3 ms). To our surprise, ifenprodil did not significantly affect the strength of potentiation in slices from sham-operated rats (Fig. 4A, open triangles; 112.2 ± 3.7%, n= 6, P= 0.14). In contrast, when the TBS was applied in the presence of ifenprodil at distances of 2.0–3.2 mm from the border of a lesion, we observed a significant (P= 0.021) reduction in the strength of LTP (Fig. 4B, filled triangles; 116.0 ± 4.8%, n= 7). In summary, the ifenprodil-sensitive part of the LTP was significantly increased in the injured visual cortex (Fig. 4C, cross-hatched bars), whereas the remaining ifenprodil insensitive part of the LTP was not different between the two experimental groups (Fig. 4C, non-cross-hatched bars). In addition, we analysed the relative degrees of ifenprodil-sensitive potentiation from the data in Fig. 4A and B. Here we also observed a significantly larger (P < 0.05) fraction of ifenprodil-sensitive LTP at the border of the lesion (lesion: 56.2 ± 4.3%; sham-operated: 38.7 ± 8.2%; Fig. 4D).

View larger version (36K): [in this window] [in a new window]   Figure 4.  NMDA receptors containing the NR2B subunit mediate the increase of LTP post-lesion A, average voltage trace of FPs recorded before (1) and following TBS (2) in control tissue in the presence of ACSF containing 3 µM ifenprodil. The summary diagram indicates no significant effect of ifenprodil on the level of LTP in sham-operated tissue. B, the same LTP experiments were repeated in slices at the border of the injury. The summary diagram shows a significant reduction of LTP in the presence of ifenprodil at the border of the lesion. C and D, the ifenprodil-insensitive part of the LTP was not different between the 2 experimental groups (C, non-cross-hatched bars), whereas the ifenprodil-sensitive part of the LTP was absolutely (C, cross-hatched bars) and relatively (D) larger (P < 0.05) in slices from lesion-treated rats.

View larger version (28K): [in this window] [in a new window]   Figure 5.  Enhanced proportion of NMDARs containing the subunit NR2B in cortical neurones at the border of the lesion A, pharmacologically isolated NMDAR-FPs from a control (1–3), and in a slice at 0.8 mm (4–6) and at 2.8 mm (7–9) from the border of the lesion. Averaged recordings of 10–1 min before ifenprodil (1, 4, 7), 81–90 min after application of ifenprodil (2, 5, 8) and in the presence of ifenprodil plus D-AP5 (3, 6, 9). B, the summary graph shows the mean reduction of the FP integral at 81–90 min following bath application of ifenprodil. Note the significantly stronger reduction of FP integrals in slices at a distance of 2.0–3.2 mm from the border of the lesion.

	Discussion

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This spatial profile of the enhanced LTP might reflect the functional reorganization of cortical area 18a after changes in the input from the lesioned cortex area 17/18 (Johnson & Burkhalter, 1994). Functional alterations in areas downstream of the zone actually injured have also been observed with a retinal lesion model in cats in vivo, where a higher excitability was observed in area 17 of the visual cortex (Eysel et al. 1999).

When we repeated the LTP experiments in the presence of the specific NMDAR-subunit antagonist, ifenprodil, at a concentration (3 µM) which is known to selectively block NR2B subunit-mediated NMDAR currents (Williams, 1993), and which was used to investigate the involvement of NR2B subunits in synaptic plasticity in development (Quinlan et al. 1999) and LTP (Lu et al. 2001), we found no effect on LTP of controls but a significant effect on the enhanced LTP in the surround of the cortical lesions. This indicates (1) that the expression of LTP in our control tissue was primarily independent of activity of the NR2B subunit; and (2) that the enhanced potentiation of FPs post-lesion was mediated by NR2B subunit-containing NMDARs. In fact, enhanced potentiation of FPs in the lesioned cortex could be mediated by alterations in the subunit composition of NMDARs (Hestrin, 1992). This is also compatible with data showing that NMDARs containing the NR2B subunit are characterized by EPSC kinetics with relatively longer decay time constants (Monyer et al. 1994) and with increased Ca²⁺ influx into the postsynaptic cell, which could cause increased levels of LTP (Carmignoto & Vicini, 1992). Furthermore, the different intracellular C-termini of the NR2 subunits are suggested to mediate synaptic plasticity, since they serve as a critical scaffold for complex intracellular signal transduction cascades (Sprengel et al. 1998; Husi et al. 2000).

To identify the fraction of NR2B subunit-containing NMDARs we investigated lesion-induced changes in the sensitivity of pharmacologically isolated NMDAR-FPs to ifenprodil and found an increased number of NMDARs containing the NR2B subunit at the border of the lesion. A larger fraction of NMDARs containing the NR2B subunit combined with an enhanced synaptic plasticity has been observed in the developing visual (Quinlan et al. 1999) and somatosensory cortex (Barth & Malenka, 2001). This suggests that the increased LTP in our lesion model might share similar mechanisms, as can be observed during the postnatal development of the visual cortex. Furthermore, it has been reported that overexpression of the NR2B subunit in forebrains of transgenic mice led to enhanced LTP in the hippocampus, and these animals exhibited a superior ability in learning and memory in various behavioural tasks (Tang et al. 1999).

However, the possible participation of the NR2B subunit in synaptic plasticity is controversially discussed. Firstly, Liu et al. (2004) reported that the induction of LTD but not LTP in area CA1 of the hippocampus is abolished by pharmacological blockade of NMDARs containing the NR2B subunit, whereas inhibition of the NR2A subunit prevented induction of LTP without affecting the LTD production. Secondly, the isolated transgenic overexpression of NR2B did not change synaptic plasticity in the visual cortex (Philpot et al. 2001). An extended duration of the critical period was not observed in a knock-out mouse model of the NR2A subunit, despite of the fact that the NMDAR subunit composition remained immature with high levels of NR2B-containing NMDARs (Lu et al. 2001). Accordingly, an increased proportion of NMDARs containing the NR2B subunit might not be the only cause for the post-lesion facilitated LTP.

Recent lesion studies from our laboratory disclosed two cellular mechanisms which can additionally contribute to the enhanced LTP. (1) Neurones located at the border of the injury showed an increased level of resting calcium concentration that was sensitive to blockers of both NMDARs and AMPARs (Barmashenko et al. 2001). Furthermore, an increased level of FP-correlated calcium influx was observed in LTP experiments post-lesion. These results are in agreement with the hypothesis that brain injuries may also modify the subunit composition of AMPA receptors by reducing the proportion of the GluR2 subunit (Gorter et al. 1997). A reduced level of the GluR2 subunit alters the functional properties of AMPA receptors and introduces a calcium permeability, which can be detected under physiological conditions only in the young neocortex at postnatal days < 15 (Kumar et al. 2002). This suggests that the enhanced synaptic plasticity in our lesion model might be based on activity of NMDA receptors containing the NR2B subunit as well as calcium-permeable AMPA receptors with reduced levels of the GluR2 subunit. (2) In earlier studies we reported a lesion-induced suppression of the inhibitory function in rat neocortex (Mittmann et al. 1994). This imbalance in excitatory and inhibitory function post-lesion can also contribute to the facilitated LTP, since it is known that a reduced inhibition facilitates synaptic strengthening in white-matter-evoked LTP in layer III (Artola & Singer, 1987) and NMDAR-independent layer-IV-evoked LTP (Huemmeke et al. 2002). However, the isolated attenuation of the GABAergic inhibition does not essentially alter NMDAR-dependent layer-IV-evoked LTP in layer III, since the total GABAergic input from layer IV to layer III is doubled between P21 and P35 (Morales et al. 2002) without affecting the magnitude of this type of LTP (Kirkwood et al. 1995).

In summary our lesion model induces complex changes to the function of the visual cortex including an NR2B subunit-mediated increase of synaptic long-term plasticity, which could support the early functional reorganization of the injured visual cortex.

	References

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	Acknowledgements

 
This study was supported by the DFG (SFB 509, TP C4). The authors thank Petra Hentrich and Ute Neubacher for excellent technical assistance. We also thank Simon Rumpel and Kurt Gottmann for suggestions and comments on the manuscript.

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This Article Abstract Full Text (PDF) All Versions of this Article: 559/3/875    most recent jphysiol.2004.069534v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huemmeke, M. Articles by Mittmann, T. Search for Related Content PubMed PubMed Citation Articles by Huemmeke, M. Articles by Mittmann, T.