Kainate receptor (GluR5)-mediated disinhibition of responses in rat ventrobasal thalamus allows a novel sensory processing mechanism

doi:10.1113/jphysiol.2003.045096

Kainate receptor (GluR5)-mediated disinhibition of responses in rat ventrobasal thalamus allows a novel sensory processing mechanism

K. E. Binns, J. P. Turner and T. E. Salt

Department of Visual Science, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK

ABSTRACT

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Abstract
Introduction
Methods
Results
Discussion
References

Kainate receptors have been studied extensively in vitro, but how they might function physiologically remains unclear. We studied kainate receptor modulation of synaptic responses in the rat ventrobasal thalamus using the novel antagonist LY382884 and the agonist ATPA (selective for GluR5-containing kainate receptors) as tools. No evidence could be found for a direct contribution of kainate receptors to responses of thalamic relay cells to lemniscal (sensory) input in thalamic slices studied with the aid of intracellular and field potential recordings, using selective AMPA and NMDA receptor antagonists and LY382884. However, the GluR5 agonist ATPA reduced the IPSPs originating from the thalamic reticular nucleus. Extracellular single-neurone recordings in anaesthetised rats showed that excitatory responses evoked by physiological vibrissa afferent stimulation were reduced by LY382884 applied iontophoretically at the recording site. This action of the antagonist was occluded when GABA receptors were blocked, indicating that the reduction in excitatory sensory responses by LY382884 is due to an action on GABAergic inhibition arising from the thalamic reticular nucleus. Further experiments showed that these actions depended on whether inhibition was evoked during activation of the excitatory receptive field rather than when inhibition was evoked from a surround vibrissa. We suggest that GluR5 is located presynaptically on inhibitory GABAergic terminals of thalamic reticular nucleus neurones, and that it is normally activated by glutamate spillover from synapses between excitatory afferents and relay neurones during physiological stimulation. We propose that this GluR5-activated disinhibition has an important novel role in extracting sensory information from background noise.

(Received 11 April 2003; accepted after revision 16 June 2003; first published online 8 August 2003)
Corresponding author T. E. Salt: Department of Visual Science, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK. Email: t.salt{at}ucl.ac.uk

INTRODUCTION

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Abstract
Introduction
Methods
Results
Discussion
References

The ventrobasal thalamus (VB) is a pivotal nucleus in the transmission of somatosensory information as it ascends to the cerebral cortex (Jones, 1985). At this point of the neuraxis there is a complex interplay between excitatory and inhibitory synaptic mechanisms, which can gate and process sensory information (Sherman & Guillery, 1996). Glutamatergic afferents from subcortical and cortical regions of the somatosensory pathways synapse in the VB, where both ionotropic and metabotropic glutamate receptors participate in the generation of sensory responses (Salt & Eaton, 1996). In addition, there is an extensive GABAergic input that arises from the thalamic reticular nucleus (TRN). It is known that both AMPA- and kainate-type glutamate receptors are found in the thalamic relay nuclei and TRN. AMPA receptors are located primarily on the postsynaptic structures of thalamic neurones (Liu, 1997; Mineff & Weinberg, 2000). In contrast, the exact synaptic location of kainate receptors is still undetermined, although they are known to be present in both the thalamic relay nuclei and the TRN (Monaghan & Cotman, 1982; Bettler et al. 1990; Wisden & Seeburg, 1993; Petralia et al. 1994).

There are several different kainate receptor subunits (GluR5-7, KA1 and KA2) that can co-assemble to form heteromeric kainate receptors (Cui & Mayer, 1999; Paternain et al. 2000). This potential functional diversity (Lerma et al. 2001) is manifested by numerous in vitro studies that have suggested presynaptic roles for kainate receptors in modulating excitatory (Chittajallu et al. 1996; Frerking et al. 2001) and inhibitory (Clarke et al. 1997; Rodriguez-Moreno et al. 1997; Ali et al. 2001; Cossart et al. 2001) transmission in the CNS, as well as postsynaptic actions (Castillo et al. 1997; Vignes & Collingridge, 1997) and actions on axons (Agrawal & Evans, 1986; Semyanov & Kullmann, 2001). Furthermore, it has been suggested that these receptors can be activated by glutamate spilling over from synapses (Min et al. 1999) or released from the cell soma or dendrites (Ali et al. 2001). This multiplicity of actions makes it difficult to predict the effects of kainate receptor-mediated modulation on overall network behaviour in vitro (Semyanov & Kullmann, 2001). Indeed, how or whether these complex actions might interact under physiological conditions in vivo is still unknown. Recently, pharmacological tools that can selectively activate and block kainate receptors have become available, particularly those containing the GluR5 subunit that can be selectively activated by the agonist ATPA (Clarke et al. 1997) and blocked by the antagonist LY382884 (Bortolotto et al. 1999). Thus, as GluR5 is present in the thalamus (Bettler et al. 1990; Paschen & Djuricic, 1994; Bernard et al. 1999), we have used these agents in order to probe the function of GluR5-containing receptors in the thalamic circuitry. We found that activation of these receptors reduces GABAergic synaptic inhibition. Furthermore, in vivo, this inhibition is dependent on the location of stimuli within receptive fields and so provides a novel synaptic mechanism that can allow glutamatergic synaptic activity to overcome GABAergic synaptic inhibition in establishing receptive field properties in the thalamus. Some of these results have been presented in abstract form (Binns et al. 2002).

METHODS

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Abstract
Introduction
Methods
Results
Discussion
References

All experiments were carried out on rats of either sex in accordance with the UK Animals (Scientific Procedures) Act, 1986 and associated guidelines, and were subject to a local ethical review procedure.

In vitro studies

Rats (60-200 g) were anaesthetised with halothane until reflexes were absent, and then decapitated. Their brains were then rapidly removed and placed in ice-cold (1-3 °C), continuously oxygenated (95 % O₂/5 % CO₂) Krebs medium containing (mM): sucrose 202, KCl 3, KH₂PO₄ 1.25, MgSO₄ 5, CaCl₂ 1 and NaHCO₃ 26. The NaCl normally used to make up the solution was replaced with an isosmotic concentration of sucrose to reduce tissue trauma during slice preparation. A coronal cut was made through the brain in front of the thalamus, and another at the level of the superior colliculus. A horizontal cut was then made along the cerebral cortex above the level of the hippocampus, and the resulting dorsal surface of the brain was glued to the cutting stage of a Vibroslice (Campden Instruments). Horizontal slices of thalamus (300 µm thick) containing the VB and the adjacent TRN and internal capsule were prepared. These slices were then placed in a storage chamber, where they were maintained in continuously oxygenated Krebs medium of the same composition as that used for slice cutting, at room temperature (20-22 °C). After 1 h, this medium was replaced by a continuously oxygenated Krebs medium containing (mM): NaCl 124, KCl 3, KH₂PO₄ 1.25, MgSO₄ 1, CaCl₂ 2, NaHCO₃ 26 and glucose 10. After a further hour, slices were transferred to an interface recording chamber where they were perfused with the same continuously oxygenated Krebs medium. For most of the experiments, this medium also contained the AMPA antagonist 1-(4-amino-phenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine (GYKI52466, 100 µM) or (±)-4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine (SYM 2206, 50 µM) and the NMDA antagonists D(-)-2-amino-5-phosphonopentanoate (AP5, 100 µM) and (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine (MK-801, 3 µM).

Using the current-clamp technique, intracellular recordings were made with sharp standard-walled glass microelectrodes (TF120, Clark Electromedical) filled with 1 M potassium acetate (final tip resistance: 80-120 M $Omega$ ). To activate the sensory input to VB neurones, a bipolar stimulating electrode was placed in the medial lemniscus. Alternatively, to generate IPSPs of TRN origin, a bipolar stimulating electrode was placed on the border of the VB and TRN. Stimulation at low frequency (0.1 Hz) using 100 µs square wave pulses of current 30-500 µA evoked a complex postsynaptic response composed of an EPSP (presumably arising from activation of corticothalamic axons that pass through the TRN en route to the VB) followed and truncated by an IPSP. Input resistance was determined by measuring the voltage drop due to passing a -0.05 or -0.1 nA current pulse through the electrode. Following amplification with an Axoprobe 1A (Axon Instruments), voltage and current records were digitised directly at 10 kHz via a micro-1401 interface, and analysed using Spike2 software (Cambridge Electronic Design).

In vivo iontophoresis studies

Rats (250-400 g) were anaesthetised with urethane (1.2 g kg^-1 I.P.) and prepared for recording as detailed previously (Salt, 1987). Throughout the experiments, heart rate and the electroencephalogram were monitored. Additional urethane anaesthetic was administered I.P. as needed, and the subjects were killed at the end of the experiment with an overdose of the same anaesthetic. Seven-barrel recording and iontophoretic glass pipettes were advanced into the thalamus, and single neuronal extracellular recordings were made from individual relay neurones responding to air-jet stimulation of individual vibrissae (Salt, 1987). The central recording barrel of the pipette was filled with 4 M NaCl. On each occasion, one of the outer barrels was filled with 1 M NaCl for current balancing and one with pontamine sky blue dye for marking recording sites. The remaining barrels were filled with a range of kainate, AMPA and NMDA receptor agonists including ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid, 20 mM in 150 mM NaCl, pH 8), iodowillardiine ((S)-1-(2-amino-2-carboxyethyl)-5-iodopyrimidine-2,4-dione, 2 mM in 150 mM NaCl, pH 8.5), AMPA (10 mM in 150 mM NaCl, pH 8), fluorowillardiine ((S)-(-)- $alpha$ -amino-5-fluoro-3,4-dihydro-2,4-dioxo-1(2H) pyridinepropanoic acid, 2 mM in 150 mM NaCl, pH 8.5) and NMDA (50 mM in 150 mM NaCl, pH 8). For each experiment, a single barrel was filled with LY382884 (4 mM in water, pH 9). The GABA_A antagonist SR95531 (50 mM in 150 mM NaCl, pH 3.5), the cholinergic agonist carbachol (carbamylcholine chloride, 200 mM in water, pH 4) and the NMDA receptor antagonist AP5 (50 mM in 150 mM NaCl, pH 8) were also used on some occasions. With the exception of SR95531 and carbachol, all drugs were ejected iontophoretically as anions, and retained by small currents of opposite polarity.

Throughout the study, action potential spikes were timed and counted using Spike2 software, which simultaneously recorded the output from the iontophoresis unit and trigger pulses initiating sensory stimuli. Data were analysed by plotting poststimulus time histograms (PSTHs) from these recordings and counting the spikes evoked by either sensory stimulation or agonist ejection. Responses in the presence of antagonist are routinely expressed as a percentage of the control response.

For each neurone, the first stage was to identify the 'principal vibrissa' (i.e. the whisker in the centre of the receptive field). Air-jet stimuli were directed only onto the principal whisker, unless otherwise stated.

The effects of LY382884 on sensory and agonist responses

Cycles consisting of sensory stimulation and brief ejection periods (10-15 s) of two or three different agonists, lasting 300-360 s were established and repeated continuously whilst recording from neurones. Care was taken to ensure that increases in cell firing frequency evoked by agonist ejections were submaximal. Sensory stimuli consisted of 5-10 electronically gated, 1000 ms air jets directed at the principal whisker, with 5-10 s interstimulus intervals. After several control cycles showed consistent results, antagonists were ejected iontophoretically during two or three cycles. The effects of the antagonist application were monitored and the current adjusted so that it normally had an effect on the sensory response, but had no effect on responses to either NMDA or AMPA receptor agonists. After cessation of antagonist ejection, cycles were continued until all responses returned to control levels.

The effects of LY382884 during blockade of GABA receptors

On some neurones, after the effects of a particular ejection current (and duration) of LY382884 had been established using cycles as above, new cycles were established consisting of periods of somatosensory stimulation (as above) alone, beginning every 150 s. After several control cycles, the GABA_A receptor antagonist SR95531was applied continuously using an iontophoretic current (25-80 nA), which produced a gradual increase in the responses to sensory stimulation. Once a new steady state had been achieved, LY382884 was ejected at the same current and duration as determined previously. In some experiments the NMDA receptor antagonist AP5 was also used in place of LY382884. The effects of the antagonists on the sensory responses in the absence and presence of GABA antagonist were compared.

The effects of LY382884 on excitatory and inhibitory sensory responses

For a further group of neurones, we identified the 'principal' whisker and a 'secondary' whisker, whose stimulation did not evoke an excitation, but which did inhibit responses to principal whisker stimulation. The secondary whisker was normally in the same row, but removed from the principal whisker by one or two places. Then a 360 s cycle was constructed consisting of a series of 10-12 air-jet stimuli directed at the principal whisker, a brief (10-12 s) period when NMDA was ejected to evoke action potential firing, and a prolonged (40-50 s) period of carbachol ejection at a current that evoked steady action potential firing, during which the secondary whisker was stimulated with a similar protocol to the principal whisker. The degree of inhibition produced when the secondary whisker was stimulated was quantified by plotting cumulative PSTHs of action potential spikes in relation to the stimulus onset. Such PSTHs show the increase in background firing rate induced by the application of carbachol and an obvious inhibitory period during stimulation of the secondary whisker (see Fig. 5B). Spikes counted during secondary whisker stimulation are expressed as a percentage of the background level. After several consistent control cycles, LY382884 was applied over two or three further cycles at an ejection current that caused a reduction of the response to the principal whisker, but had no effect on the response to NMDA. After the cessation of antagonist ejection, cycles were continued until all responses returned to control levels.

RESULTS

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Abstract
Introduction
Methods
Results
Discussion
References

Modulation of IPSPs by GluR5-containing receptors in vitro

In order to determine the effects of activating GluR5-containing receptors on VB neurones, we made intracellular current-clamp recordings from neurones in the thalamic slice preparation. Stimulation of the medial lemniscus at low frequencies (0.1 Hz) evoked an EPSP in thalamic relay neurones. This was blocked when a combination of the AMPA antagonist GYKI52466 (100 µM) together with the NMDA antagonists AP5 (100 µM) and MK-801 (3 µM) was added to the bathing medium. Under these conditions, the frequency of stimulation of lemniscal afferents was increased to trains of 50 Hz, but this did not reveal any additional synaptic components in five neurones tested in this way, as illustrated in Fig. 1A. As it is known that kainate receptors are not blocked by this combination of antagonists, this suggests that there is no contribution of kainate receptors to the excitatory response of relay cells to sensory input, as has also recently been shown by others (Bolea et al. 2001).

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Figure 1
A, responses of a thalamic relay neurone to stimulation of the medial lemniscus (100 µA). A1 shows five superimposed EPSPs (each evoking an action potential) in response to 0.1 Hz stimulation either under control conditions or following perfusion of AMPA and NMDA antagonists (GYKI52466 plus MK-801 plus AP5). The antagonists completely blocked the EPSP, as can also be seen in the overlay of averaged responses (n = 5). A2 shows the same neurone in the continued presence of the AMPA and NMDA antagonists, with 1 s trains of 50 Hz medial lemniscus stimulation (five superimposed responses) in an attempt to reveal additional synaptic response components. No further responses were revealed by this stimulation protocol. B, IPSPs recorded in response to stimulation of the TRN in the presence of GYKI52466, AP5 and MK-801. In the upper row, each trace is an average of responses to 10 repeated stimuli applied to the TRN (presented at the time indicated by the arrowhead). Application of ATPA to the bathing medium reduced the IPSP amplitude after 5 min, and this effect was reversed when LY382884 was then added for 10 min. The right panel shows superimposed traces from the panels on the left. The lower row of traces shows averaged responses to a -0.1 nA current pulse injected through the recording electrode.

Further experiments were carried out in the presence of the AMPA and NMDA antagonist combination. Stimulation of the TRN revealed an isolated IPSP under these conditions. Recordings were made from 14 such neurones (which had a resting membrane potential of -62 ± 0.74 mV and an input resistance of 117 ± 15 M $Omega$ ), and the peak amplitude of the IPSP recorded was -3.2 ± 0.6 mV. Bath application of the GluR5 agonist ATPA caused a reversible reduction of IPSP amplitude from -3.0 ± 0.6 mV to -2.4 ± 0.6 mV (P < 0.001, Student's paired t test) within 10 min in 12 neurones when it was applied at either 10 µM (n = 2) or 20 µM (n = 10; Fig. 1B), representing a reduction of 24 %. Conversely, application of 5 µM ATPA (n = 2) had no discernable effect on IPSP amplitude. The effect of ATPA was reversed within 10 min of returning to a bathing solution that did not contain the agonist. Overall, the application of ATPA caused no significant change in either input resistance (112 ± 14 M $Omega$ ) or membrane potential (61 ± 0.9 mV). In four neurones, the antagonist LY382884 (10 µM, a concentration known to be selective for GluR5-containing kainate receptors; Lauri et al. 2001), was added to the perfusion medium in addition to ATPA, and this reversed the depression of the IPSP caused by ATPA from a mean of 26 ± 4.9 % to a mean of 2 ± 2.3 % (Fig. 1B).

It was important to verify that LY382884 had no direct effect on the glutamatergic transmission from the medial lemniscus when used at the same concentration that was effective against GluR5 activation, as this would affect the interpretation of our results. We thus made field-potential recordings when the medial lemniscus was stimulated with five stimuli at either 10 or 20 Hz in the presence of GABA_A and GABA_B antagonists (100 µM picrotoxin and 3 µM CGP55845, respectively). This gave rise to field EPSPs that reduced in amplitude during the train (Turner & Salt, 1998; Castro-Alamancos, 2002). Addition of 10 µM LY382884 had no significant effect on these EPSPs or on the depression of the EPSPs in the train (Fig. 2). These findings indicate that LY382884 can act at GluR5-containing receptors, modulating inhibition in the VB without directly affecting excitatory synaptic transmission from the lemnsical (sensory) afferents.

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Figure 2. Field EPSPs recorded in response to stimulation of the medial lemniscus (five at 20 Hz)
Each trace (A-C) is an average of 10 responses to stimulus bursts presented at a rate of 0.1 Hz. All data were obtained in the presence of GABA_A and GABA_B receptor antagonists (100 µM picrotoxin and 3 µM CGP55845). A, responses to the five stimuli under control conditions (with GABA antagonists), 15 min after addition of LY382884 (10 µM) to the bath, and after 15 min washout (Wash) of this antagonist. B, enlarged traces showing field EPSPs in response to the first (EPSP1) and second (EPSP2) stimuli of each train shown in A. C, overlay of EPSP1 and EPSP2 responses obtained under control conditions and during LY382884 application. D, averaged data (± S.E.M.) from five experiments. Field EPSPs have been normalised as a percentage of EPSP1 under control conditions. LY382884 had no significant effect on EPSPs or on the ratio of EPSP2 to EPSP1 or EPSP5 to EPSP1.

The effects of the GluR5 antagonist LY382884 on agonist and sensory responses in vivo

A major objective of the present study was to determine whether GluR5-containing kainate receptors play a part in somatosensory transmission in the VB under physiological conditions. In order to investigate this, we initially tested the effects of LY382884 on 15 neurones with vibrissal receptive fields that were responsive to air jets directed at the appropriate whisker. A range of agonists with putative selectivity for AMPA and kainate receptors was applied iontophoretically, and NMDA was included for control purposes. In this study both AMPA and NMDA were found to excite thalamic neurones in a manner that was expected from previous work from this and other laboratories (Salt & Eaton, 1996). Fluorowillardiine is a novel compound that is selective for GluR1 and GluR2, with some activity at GluR4 receptors (Jane et al. 1997), while iodowillardiine and ATPA show selectivity for GluR5 subunits (Clarke et al. 1997; Jane et al. 1997). All three of these agonists were found to excite thalamic neurones in a manner similar to AMPA. Example data for fluorowillardiine and ATPA are shown in Fig. 3. Iontophoretic ejections of LY382884 reduced the responses of thalamic neurones to vibrissal stimulation to 50.0 ± 5.7 % of control (n = 15, P < 0.001, Wilcoxon matched-pairs test), as shown in Fig. 3. However, in most cases (10 out of 15) these reductions were not accompanied by reductions in responses to agonists, and overall there was no significant reduction in the responses to any of the agonists including iodowillardiine and ATPA (Table 1). Although LY382884 failed to block responses to the kainate receptor-selective agonists, we were satisfied that the effects of this antagonist on sensory responses were not due to a non-specific action on glutamate receptors in general, since at the ejection currents used, responses of the same neurones to NMDA and fluorowillardiine were also unaffected.

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Figure 3. Effect of LY382884 on sensory and agonist responses of a VB neurone
PSTHs of action potential spikes counted into epochs of either 200 ms (A-C) or 1000 ms (D), recorded from a VB neurone in vivo. A-C, cumulative histograms of the responses to five air-jet stimuli to the principal vibrissa (B4) before, during and after the iontophoretic application of LY382884. Note the reduction of vibrissal responses by the antagonist. Arrows indicate the time points in D from where these histograms were computed. D, continuous record from the same neurone in response to regular sensory stimulation of the principal vibrissa with groups of five air jets and iontophoretic ejections of NMDA, ATPA and fluorowillardiine (Fluoro), as indicated by the marker bars beneath the record. Continuous ejection of LY382884 (marker bar) resulted in a reduction of the responses to vibrissal stimulation, with little effect on responses to iontophoretically applied agonists.

The effect of LY382884 during blockade of GABAergic transmission

It is known that vibrissa stimulation also evokes a recurrent inhibition in VB neurones, which arises from the neurones in the TRN and is mediated by GABA_A receptors (Salt, 1989; Lee et al. 1994; Hartings & Simons, 2000). Since LY382884 was able to reduce vibrissa-evoked excitatory responses without affecting excitatory responses of the same neurones to any of the ionotropic glutamate receptor agonists, and as ATPA reduced TRN-evoked IPSPs in vitro, it is conceivable that the effect of LY382884 is due to the positive modulation of GABA transmission. In order to test this hypothesis, we blocked GABA_A receptor-mediated transmission with SR95531, and then applied LY382884, as shown in Fig. 4. Under control conditions, LY382884 reduced the response of this neurone to the vibrissa stimulus to 38 % of the control. When SR95531 was applied, sensory responses were enhanced. This is due to the known reduction of the recurrent GABAergic inhibition, which is activated by sensory stimulation in vivo, resulting in an enhancement of sensory responses, rather than an antagonism of tonically active GABAergic inhibition (Salt, 1989; Lee et al. 1994; Hartings & Simons, 2000). Under these conditions, when LY382884 was applied in the presence of SR95531 it failed to reduce the sensory response. Pooled data from five neurones studied in this way are shown in Table 2, and these indicate that the effect of the LY382884 under these two conditions was significantly different (P < 0.05, Wilcoxon matched-pairs test). For comparison, we studied the effects of the NMDA receptor antagonist AP5 on sensory responses in the absence and presence of SR95531. Under normal conditions, NMDA receptor-selective applications of AP5 reduce the response to air-jet stimulation by blockade of postsynaptic receptors on relay neurones (Salt, 1986), and in the present study the effects of AP5 were less prominent than those of LY382884. However, in spite of this, the effects of AP5 on sensory responses in the absence (51 ± 3 % of control) and presence (49 ± 2 % of control) of SR95531 were similar for all six neurones studied in this way (P > 0.1, see Table 2). Thus, it appears that the mechanism by which LY382884 reduces sensory responses depends on intact GABAergic inhibition impinging upon the VB relay neurones, rather than a non-selective excitability change.

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Figure 4. Reduction of LY382884 effect by a GABA antagonist
A series of PSTHs showing the cumulative response of a VB neurone when air jets were presented to its principal whisker (B3). Five stimuli were presented with a 10 s interstimulus interval. Action potential spikes were collected in 200 ms bins. The PSTHs show: a, the control response; b, the reduction of the response when LY382884 was ejected; c, the return of the response to control levels after cessation of antagonist ejection; d, a control response; e and f, the increase in the response when 20 nA SR95531 was applied; g and h, the effects of LY382884 during the ejection of SR95531; and i, the final response after cessation of LY382884 ejection but in the presence of SR95531. For this neurone, the responses to NMDA and ATPA were, respectively, 92 and 91 % of the control level during the ejection of LY382884. The records were taken at 5 min intervals.

Principal vibrissa stimulation is needed to activate GluR5 receptors

As the inhibitory action of LY382884 on sensory responses appears to require the presence of GABAergic inhibition, we wondered whether excitatory glutamatergic transmission was also a requirement in this process. As the recurrent GABAergic inhibition arising from the TRN also has lateral effects (Pinault & Deschenes, 1998), it is possible to present vibrissal stimuli that generate only inhibitory responses on VB neurones (Salt, 1989). Such responses can be generated by stimulation of a vibrissa that is adjacent or near to the principal vibrissa of the neurone under investigation (Fig. 5A). To reveal such inhibitory actions of vibrissal stimulation, we ejected the cholinergic agonist carbachol in order to elevate the ongoing firing rate of neurones, and then presented air-jet stimuli to a non-principal vibrissa (Fig. 5B).

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Figure 5. The effect of LY382884 on responses to principal and secondary whisker stimulation
A1, the route of activation of inhibitory neurones during principal whisker stimulation, as indicated by the arrows from the afferent onto the relay cell (RC) and then onto the TRN cell. A2, the route during secondary whisker stimulation. B1, histograms from a VB neurone where stimulation of the principal (B4) vibrissa elicited an excitatory response. The cumulative response to 12 air jets directed at the B4 whisker is shown during the control period (left), after ejecting LY382884 for 10 min (centre), and 10 min after the cessation of antagonist ejection (right). LY382884 reduced the response to stimulation of whisker B4. B2, histograms from the same neurone illustrating the inhibition produced by stimulating the B2 whisker when the baseline activity of the neurone was elevated by ejection of carbachol. The cumulative activity during 10 stimulation cycles with an air jet directed at the B2 whisker is shown during the control period (left), after ejecting LY382884 for 10 min (centre), and 10 min after the cessation of antagonist ejection (right). LY382884 did not increase the degree of inhibition in these circumstances. The inset shows the relative positions of whiskers B4 and B2, stimulation of which produced excitation and inhibition, respectively.

Data acquisition cycles were constructed to include a series of 1000 ms air jets directed at the secondary vibrissa on a background of carbachol ejection. This vibrissal stimulation resulted in an inhibition of the carbachol-evoked elevation of firing (Fig. 5B2). In order to verify that LY382884 was affecting the principal vibrissa responses on the same neurone, we also included principal whisker stimulation and NMDA ejection (both without carbachol ejection) in the stimulus cycles. After control data had been obtained, LY382884 was applied. LY382884 reduced the excitatory response to stimulation of the principal vibrissa while having little effect on the response to NMDA, as before, thus indicating that there was a selective effect of the antagonist on principal vibrissa responses. Figure 5B shows data from a neurone studied in this way and illustrates the typical effects of LY382884. Overall, on eight neurones LY382884 reduced the response to stimulation of the central vibrissa to 61 ± 5 % of the control response, while the responses to NMDA and carbachol remained close to control values (108 ± 9.4 % and 112 ± 18 % of control, respectively). In the presence of carbachol, stimulation of a non-principal vibrissa decreased the firing rate of the same cells to 58 ± 5.6 % of control (P < 0.01, Wilcoxon matched-pairs test). We hypothesised that if the effect of LY382884 does not depend on principal vibrissa input, then we would expect to see a further decrease in firing rate when the antagonist is applied. However, this was not seen and the stimulus-evoked inhibition was not increased when LY382884 was applied (responses reduced to only 77 ± 12.4 % of control, not significantly different to the inhibitory response seen prior to LY382884 ejection). These data are summarised in Fig. 6. Furthermore, the activity evoked by carbachol ejection was not significantly different during LY382884 application (94 ± 8.9 % of control). These data imply that stimulation of the principal whisker, which directly activates the thalamic relay neurone, is necessary for the activation of kainate receptors and their subsequent effects on inhibition.

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Figure 6. Average data from eight neurones where the effects of LY382884 on responses to principal vibrissa stimulation and secondary vibrissa stimulation were investigated
A, effects of the antagonist on excitatory responses to principal vibrissa stimulation and to iontophoretically applied NMDA and carbachol. Values are expressed as percentages (± S.E.M.) of the value prior to antagonist ejection. B, effects of the antagonist on inhibitory responses to secondary vibrissa stimulation. Values are percentages of the carbachol response (± S.E.M.) before and during LY382884 ejection (see text for details).

DISCUSSION

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Abstract
Introduction
Methods
Results
Discussion
References

The study of the role of kainate receptors in sensory function is in its relative infancy, although there are data to suggest that some of the kainate receptors participate in spinal cord synaptic responses (Procter et al. 1998; Li et al. 1999; Kerchner et al. 2001b). However, little is known about how kainate receptors may contribute to synaptic function in vivo. The data that we have obtained using selective agonists and antagonists of the GluR5 subunit of kainate receptors both in vivo and in vitro in the rat VB clearly demonstrate a role for kainate receptors containing the GluR5 subunit in sensory transmission. Firstly, we demonstrated that in the thalamic slice, activation of GluR5-containing kainate receptors resulted in a reduction of GABAergic IPSPs, while kainate receptors do not appear to be involved in the lemniscal input to these neurones. Secondly, using a natural stimulation protocol and iontophoresis in vivo, we demonstrated that blockade of GluR5-containing receptors with LY382884 results in the reduction of excitatory responses to stimulation of principal vibrissae in the receptive field. Finally, we proceeded to show that in vivo GABAergic inhibition is a critical component of the action of LY382884 by studying the effects of this antagonist in the presence of the GABA_A receptor blocker SR95531, and that the action of LY382884 on GABAergic inhibition requires the direct excitatory activation of VB neurones via stimulation of the principal whisker.

Activation of kainate receptors reduces inhibition in the thalamus

The VB of rodents, as opposed to other mammals, is unusual in that it lacks intrinsic inhibitory interneurones and thus inhibition is derived solely from the GABAergic neurones in the TRN (Ralston, 1983; Harris & Hendrickson, 1987). Given the lack of GABAergic cell bodies in the VB, our finding that ATPA reduces the amplitude of the TRN-evoked IPSP in vitro is consistent with the location of GluR5-containing kainate receptors on the terminals of inhibitory fibres, and with a possible functional role in modulating inhibition. The location of mRNA for GluR5 and other kainate receptors within the TRN is consistent with this idea. Previous work from other laboratories in the hippocampus and cerebral cortex has provided evidence that activation of kainate receptors can reduce GABAergic transmission via a presynaptic mechanism (Clarke et al. 1997; Rodriguez-Moreno et al. 1997; Ali et al. 2001), and the magnitude of the effect seen in the present study is similar to that seen on evoked inhibitory synaptic events in other brain areas (Min et al. 1999). For other brain areas, it has been suggested that the reduction of IPSPs or IPSCs seen upon kainate agonist application could be due to intense excitation of interneurones or their axons (Semyanov & Kullmann, 2001), or a direct action on GABAergic terminals (Kerchner et al. 2001a), resulting in the release of GABA, which then acts on presynaptic autoreceptors, thus reducing the IPSP/IPSC. Such a mechanism would, however, also be expected to result in a large postsynaptic GABA response, which would cause a large decrease in postsynaptic membrane resistance. Such effects were not seen in this study, and reductions in IPSP amplitude could not be accounted for in terms of changes in membrane resistance.

An important issue in these in vitro experiments is the selectivity of the pharmacological agents. On hippocampal neurones, the EC₅₀ of ATPA for reduction of IPSPs has been shown to be 2 µM, and the dose used for functional studies was 10 µM (Clarke et al. 1997). The dose used in our study is close to this, representing a maximally effective concentration at these receptors. Nevertheless, this is still substantially lower than the dose required to act at other receptors (Bortolotto et al. 1999), and it may be that the relatively high dose we have used is due to the particular heteromeric composition of the GluR5 kainate receptors present (Clarke & Collingridge, 2002). LY382884 has now been extensively characterised as an antagonist of GluR5-containing receptors, and the dose of 10 µM is one that is known to be effective at these receptors, while having little effect on a variety of other receptors (Bortolotto et al. 1999; Lauri et al. 2001). The selectivity of this dose of LY382884 for GluR5-containing receptors is underlined in the present study by the finding that it could reverse ATPA-induced IPSP reductions, whilst having no significant effect on the lemniscal field EPSPs.

VB relay neurones in vivo respond to stimulation of vibrissae via the trigeminal nuclei, the projection from the face maintaining topographic precision such that individual relay neurones receive direct dominant input from a principal vibrissa, and surrounding vibrissae have less impact, but project to other relay neurones (Diamond et al. 1992; Nicolelis & Chapin, 1994; Lee et al. 1994). Relay cells project to the TRN and cerebral cortex, the inhibitory neurones in the TRN receiving input from several vibrissae and making reciprocal projections back to the thalamus (Jones, 1985; Shosaku et al. 1989; Pinault & Deschenes, 1998). Thus, the responses of a relay neurone to stimulation of its principal vibrissa are the result of excitatory input and recurrent inhibition, whereas stimulation of surrounding vibrissae often results in only inhibition (Salt, 1989). It appears that in vivo, GluR5-containing kainate receptors, which regulate GABA transmission, are normally activated when the vibrissae are stimulated, since the application of LY382884 in our iontophoretic studies reduced excitatory responses to sensory stimulation. We are satisfied that the effects of LY382884 on sensory responses were not due to a non-specific effect of the antagonist on glutamate receptors, since the excitatory effects of agonists such as NMDA and fluorowillardiine were robust during LY382884 ejection. Furthermore, it is unlikely that LY382884 achieved its effects by a direct agonistic interaction with GABA receptors, since the direct application of GABA would be expected to inhibit both sensory and agonist responses (Kaneko & Hicks, 1990). We thus interpret our data on the basis that LY382884 had its effects on sensory responses in the VB through a specific blockade of GluR5-containing kainate receptors that normally reduce GABAergic transmission from the TRN. Finally, to confirm the inverse relationship between inhibition and kainate receptor activation in vivo, we studied the effects of LY382884 during the blockade of GABA_A receptors with SR95531. The failure of LY382884 to reduce sensory responses under these conditions is consistent with a circuit in which activation of presynaptic kainate receptors on GABAergic terminals normally limits the release of GABA (Fig. 5).

Interestingly, despite the profound effect that LY382884 had on sensory responses, the antagonist failed to simultaneously block the responses of the same neurones to the kainate agonists iodowillardiine or ATPA. This may have arisen through a combination of factors. Firstly, as a technical limitation of the iontophoretic technique, high drug concentrations can be delivered to very small areas so that even when selective agonists are used, inappropriate receptors can be activated. This situation would be exacerbated by two other problems: (1) the tendency of kainate receptors to be rapidly desensitised by their agonists at concentrations much below those required to elicit excitatory currents (Chittajallu et al. 1999) and (2) the very high number of AMPA receptors found at postsynaptic sites in the thalamus, which are probably responsible for mediating most of the fast excitatory activity (Mineff & Weinberg, 2000). Thus, it is likely that under our in vivo experimental conditions, any postsynaptic effect of kainate receptors may be obscured, and the excitatory effects seen with these putative kainate receptor agonists are in fact mediated by AMPA receptors. This interpretation is consistent with our observed lack of depolarising effect of ATPA in vitro while AMPA receptors are blocked with GYKI52466, and this in turn is consistent with the lack of direct excitatory effect of GluR5 activation on principal neurones in other parts of the brain (Clarke et al. 1997; Ali et al. 2001). A further noteworthy point concerning the lack of effect of LY382884 on iontophoretically applied agonists is that this indicates that the amounts of this antagonist that were ejected are unlikely to have had non-selective actions on other receptors: thus, the reduction of the sensory responses seen with LY382884 cannot be attributed to a non-specific action of this compound.

Kainate receptors may be activated by transmitter spillover

We aimed to establish the stimulation conditions that would release glutamate to activate kainate receptors in the VB during natural stimulation. If the circuit described above and depicted in Fig. 5 is broadly correct and GluR5-containing kainate receptors influence inhibition from their location on inhibitory terminals, then the most likely source of transmitter is the terminals of sensory afferents from the principal whisker. This concept is supported by the close location of sensory and inhibitory terminals to each other on the soma or proximal dendrites of VB neurones (Ohara & Lieberman, 1993). That being so, we can predict that blockade of kainate receptors with LY382884 should only influence inhibition if there is direct driving of the relay neurone by its principal vibrissa. In contrast, if inhibition is generated in the absence of excitatory activity, then LY382884 should be ineffective. Such GABAergic inhibition can be evoked by stimulation of vibrissae close to the principal vibrissa (Salt, 1989). Under our in vivo recording conditions, spontaneous activity of VB relay neurones is low, and therefore inhibition cannot be observed in the absence of direct excitation. In order to circumvent this problem and isolate inhibition without the need to stimulate the principal vibrissa or glutamate receptors, we applied the cholinergic agonist carbachol. Using this approach, inhibition can be observed on the background of a carbachol excitation. When LY382884 was then co-applied during this protocol, the level of inhibition was not increased by the application of this antagonist, while responses of the same neurone to stimulation of the principal whisker were diminished, as before. Thus, stimulation of the principal whisker is an obligatory part of the circuit that activates kainate receptors and allows them to influence inhibition (Fig. 5). Moreover, our findings indicate that the disinhibitory effect of kainate receptor activation is dependent on the local release of glutamate. Given that sensory and inhibitory terminals are close to each other, but do not make traditional axo-axonic synapses in the VB (Ohara & Lieberman, 1993), our findings are consistent with the concept of 'synaptic spillover', similar to the scheme suggested for the hippocampus by Min et al. (1999).

Kainate receptors: a functional mechanism for highlighting significant information

The data obtained in this study demonstrate clearly that kainate receptors containing the GluR5 subunit are involved in the response of VB neurones to natural somatosensory stimuli. Interestingly, both our in vivo and in vitro data provide little evidence for postsynaptic GluR5-containing receptors on relay neurones. Rather, it appears that these receptors are located on, or close to, the terminals of inhibitory axons arising from TRN cells. Furthermore, these kainate receptors appear to be activated by glutamate spillover when the sensory afferents are stimulated, thus reducing or limiting the release of GABA. This would provide a novel mechanism whereby stimulation of the sensory afferents from the centre of the receptive field is able to counteract ongoing lateral inhibition, potentiating responses to significant stimuli such that they stand out from background information, and thereby enhancing sensory discrimination. This would provide a neural 'winner takes all' or 'pop-out' mechanism (Treisman & Gelade, 1980; Nakayama & Silverman, 1986). Given the widespread distribution of kainate receptors that may modulate inhibition, such a mechanism could be of wide functional importance in signal processing.

REFERENCES

Top
Abstract
Introduction
Methods
Results
Discussion
References

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Ali AB, Rossier J, Staiger JF & Audinat E (2001). Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex. J Neurosci 21, 2992-2999 [Abstract/Full Text]

Bernard A, Ferhat L, Dessi F, Charton G, Represa A, Ben-Ari Y & Khrestchatisky M (1999). Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in vitro: evidence for independent developmental, pathological and cellular regulation. Eur J Neurosci 11, 604-616 [Medline]

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Acknowledgements

We thank C. A. Pothecary for skilled technical assistance. We are grateful to Eli Lilly (Indianapolis) for donating LY382884, Sanofi (Montpellier) for donating SR95531, and Dr I. Tarnawa (Institute for Drug Research, Budapest) for donating GYKI52466.

Authors' present addresses

K. E. Binns: Department of Zoology, Sub-department of Animal Behaviour, University of Cambridge, Cambridge CB3 8AA, UK.

J. P. Turner: Department of Optometry and Neuroscience, UMIST, PO Box 88, Manchester M60 1QD, UK.

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Agrawal SC , & Evans RH (1986). The primary afferent depolarizing action of kainate in the rat. Br J Pharmacol 87, 345-355	[Abstract]
Ali AB, Rossier J, Staiger JF & Audinat E (2001). Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex. J Neurosci 21, 2992-2999	[Abstract/Full Text]
Bernard A, Ferhat L, Dessi F, Charton G, Represa A, Ben-Ari Y & Khrestchatisky M (1999). Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in vitro: evidence for independent developmental, pathological and cellular regulation. Eur J Neurosci 11, 604-616	[Medline]
Bettler B, Boulter J, Hermansborgmeyer I, O'Shea-Greenfield A, Deneris ES, Moll C, Borgmeyer U, Hollmann M & Heinemann S (1990). Cloning of a novel glutamate receptor subunit, GluR5 - expression in the nervous system during development. Neuron 5, 583-595	[Medline]
Binns KE, Turner JP & Salt TE (2002). The role of kainate (GluR5) receptors in sensory responses of rat ventrobasal thalamus (VB) neurones. Br J Pharmacol 135, suppl., 85P
Bolea S, Liu XB & Jones EG (2001). Kainate receptors at corticothalamic synapses do not contribute to synaptic responses. Thalamus Relat Syst 1, 187-196
Bortolotto ZA, Clarke VRJ, Delany CM, Parry MC, Smolders I, Vignes M, Ho KH, Miu P, Brinton BT, Fantaske R, Ogden A, Gates M, Ornstein PL, Lodge D, Bleakman D & Collingridge GL (1999). Kainate receptors are involved in synaptic plasticity. Nature 402, 297-301	[Medline]
Castillo PE, Malenka RC & Nicoll RA (1997). Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons. Nature 388, 182-186	[Medline]
Castro-Alamancos MA, (2002). Properties of primary sensory (lemniscal) synapses in the ventrobasal thalamus and the relay of high-frequency sensory inputs. J Neurophysiol 87, 946-953	[Abstract/Full Text]
Chittajallu R, Braithwaite SP, Clarke VRJ & Henley JM (1999). Kainate receptors: subunits, synaptic localization and function. Trends Pharmacol Sci 20, 26-35	[Medline]
Chittajallu R, Vignes M, Dev KK, Barnes JM, Collingridge GL & Henley JM (1996). Regulation of glutamate release by presynaptic kainate receptors in the hippocampus. Nature 379, 78-81	[Medline]
Clarke VR , & Collingridge GL (2002). Characterisation of the effects of ATPA, a GLU(K5) receptor selective agonist, on excitatory synaptic transmission in area CA1 of rat hippocampal slices. Neuropharmacology 42, 889-902	[Medline]
Clarke VRJ, Ballyk BA, Hoo KH, Mandelzys A, Pellizzari A, Bath CP, Thomas J, Sharpe EF, Davies CH, Ornstein PL, Schoepp DD, Kamboj RK, Collingridge GL, Lodge D & Bleakman D (1997). A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 389, 599-603	[Medline]
Cossart R, Tyzio R, Dinocourt C, Esclapez M, Hirsch JC, Ben-Ari Y & Bernard C (2001). Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons. Neuron 29, 497-508	[Medline]
Cui CH , & Mayer ML (1999). Heteromeric kainate receptors formed by the coassembly of GluR5, GluR6, and GluR7. J Neurosci 19, 8281-8291	[Abstract/Full Text]
Diamond ME, Armstrong-James M & Ebner FF (1992). Somatic sensory responses in the rostral sector of the posterior group (POm) and in the ventral posterior medial nucleus (VPM) of the rat thalamus. J Comp Neurol 318, 462-476	[Medline]
Frerking M, Schmitz D, Zhou Q, Johansen J & Nicoll RA (2001). Kainate receptors depress excitatory synaptic transmission at CA3 CA1 synapses in the hippocampus via a direct presynaptic action. J Neurosci 21, 2958-2966	[Abstract/Full Text]
Harris RM , & Hendrickson AE (1987). Local circuit neurons in the rat ventrobasal thalamus - a GABA immunocytochemical study. Neuroscience 21, 229-236	[Medline]
Hartings JA , & Simons DJ (2000). Inhibition suppresses transmission of tonic vibrissa-evoked activity in the rat ventrobasal thalamus. J Neurosci 20, U15-19
Jane DE, Hoo K, Kamboj R, Deverill M, Bleakman D & Mandelzys A (1997). Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes. J Med Chem 40, 3645-3650	[Medline]
Jones EG, (1985). The Thalamus. Plenum, New York
Kaneko T , & Hicks TP (1990). GABAB-related activity involved in synaptic processing of somatosensory information in S1 cortex of the anaesthetized cat. Br J Pharmacol 100, 689-698	[Abstract]
Kerchner GA, Wang GD, Qiu CS, Huettner JE & Zhuo M (2001a). Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn. An ionotropic mechanism. Neuron 32, 477-88	[Medline]
Kerchner GA, Wilding TJ, Li P, Zhuo M & Huettner JE (2001b). Presynaptic kainate receptors regulate spinal sensory transmission. J Neurosci 21, 59-66	[Abstract/Full Text]
Lauri SE, Delany CJ, Clark VR, Bortolotto ZA, Ornstein PL, Isaac JTR & Collingridge GL (2001). Synaptic activation of a presynaptic kainate receptor facilitates AMPA receptor-mediated synaptic transmission at hippocampal mossy fibre synapses. Neuropharmacology 41, 907-915	[Medline]
Lee SM, Friedberg MH & Ebner FF (1994). The role of GABA-mediated inhibition in the rat ventral posterior medial thalamus. II. Differential effects of GABAA and GABAB receptor antagonists on responses of VPM neurons. J Neurophysiol 71, 1716-1726	[Abstract]
Lerma J, Paternain AV, Rodriguez-Moreno A & Lopez-Garcia JC (2001). Molecular physiology of kainate receptors. Physiol Rev 81, 971-998	[Abstract/Full Text]
Li P, Wilding TJ, Kim SJ, Calejesan AA, Huettner JE & Zhuo M (1999). Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 397, 161-164	[Medline]
Liu XB, (1997). Subcellular distribution of AMPA and NMDA receptor subunit immunoreactivity in ventral posterior and reticular nuclei of rat and cat thalamus. J Comp Neurol 388, 587-602	[Medline]
Min MY, Melyan Z & Kullmann DM (1999). Synaptically released glutamate reduces gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proc Natl Acad Sci U S A 96, 9932-9937	[Abstract/Full Text]
Mineff EM , & Weinberg RJ (2000). Differential synaptic distribution of AMPA receptor subunits in the ventral posterior and reticular thalamic nuclei of the rat. Neuroscience 101, 969-982	[Medline]
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