Modulation of retino-collicular transmission by Group III metabotropic glutamate receptors at different ages during development

Neuropharmacology 49 (2005) 26e34 www.elsevier.com/locate/neuropharm

Modulation of retino-collicular transmission by Group III metabotropic glutamate receptors at different ages during development C.J. Lacey 1, C.A. Pothecary, T.E. Salt * Institute of Ophthalmology, University College London, London EC1V 9EL, United Kingdom Received 26 February 2005; received in revised form 11 May 2005; accepted 8 June 2005

Abstract Group III metabotropic glutamate receptors (especially mGlu4, mGlu7, mGlu8) are thought to be involved in modulating visual processing in the adult superior colliculus, a major termination site of retinal input in the rodent brain. We have investigated this role by making field EPSP recordings in response to optic tract stimulation in superior colliculus slices taken from rats aged from P14 to P180. Application of the Group III agonist L-AP4 at a concentration (10 mM) effective to activate mGlu4 and mGlu8 receptors, but not mGlu7 receptors, resulted in reductions of the field EPSP in all ages, although the effect was greatest in slices taken from P14 rats. Increasing the L-AP4 concentration to 100 mM so as to also activate mGlu7 receptors resulted in further field EPSP reductions. Similar reductions were seen in the combined presence of the GABA antagonists picrotoxin and CGP55845A, indicating a lack of involvement of GABAergic mechanisms in the action of L-AP4. Pairing of optic tract stimuli (20 ms separation) resulted in paired-pulse depression at all ages. L-AP4 was found to reduce paired-pulse depression at both 10 mM and 100 mM in slices from all ages of rat. The results of this study suggest that mGlu4/mGlu8 and mGlu7 receptors modulate retino-tectal transmission via a presynaptic mechanism, and that these effects are greatest in young animals. This is the first demonstration of a functional change in Group III receptor effect with aging, and this would be consistent with developmental regulation of these receptors. Ó 2005 Elsevier Ltd. All rights reserved. Keywords: Superior colliculus; mGlu4; mGlu8; mGlu7; Retino-collicular transmission; L-AP4; Development; Presynaptic receptors; Metabotropic glutamate receptors

1. Introduction The superior colliculus (SC) is the major site of termination of retinofugal axons in rodents, and has an important role in the processing of visual information

* Corresponding author. Institute of Ophthalmology, Department of Visual Science, University College London, 11-43 Bath Street, London EC1V 9EL, United Kingdom. Tel.: C44 20 7608 6843; fax: C44 20 7608 6912. E-mail address: [email protected] (T.E. Salt). 1 Present address: MRC Anatomical Neuropharmacology Unit, Mansfield Road, Oxford OX1 3TH, United Kingdom. 0028-3908/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2005.06.003

and its integration with sensory information from other modalities. Retinal axons project in a retinotopic manner into the superficial grey layers of the SC, and form glutamatergic synapses onto both excitatory and inhibitory neuronal elements in these layers (Binns, 1999; Mize, 1996; Stein and Meredith, 1993). This synaptic input is mediated via ionotropic glutamate receptors with contributions from both AMPA receptors and NMDA receptors (Binns, 1999; Binns and Salt, 1998; Lo and Mize, 1999). There is now also evidence in favour of a role for metabotropic glutamate receptors in the mediation and modulation of synaptic transmission in the SC. The

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eight mGlu receptors can be classified into three groups on the basis of sequence homology, second messenger coupling, and pharmacology (Conn and Pin, 1997). Group I receptors (mGlu1 and mGlu5) typically couple to intracellular phosphoinositide hydrolysis in expression systems whereas Group II (mGlu2 and mGlu3) and Group III receptors (mGlu4, mGlu6, mGlu7 and mGlu8) typically inhibit forskolin-stimulated cAMP production (Anwyl, 1999; Conn and Pin, 1997; Schoepp, 2001). Anatomical studies demonstrate that receptors representing all three of the mGlu receptor groups are found in the rat SC (Cirone et al., 2002b; Ohishi et al., 1995, 1993; Shigemoto et al., 1992), and there is evidence that these receptors are involved in the mediation and modulation of visual transmission in the SC (Cirone et al., 2002a; Cirone and Salt, 2001; Thompson et al., 2004; White et al., 2003). In particular, we have found that Group III receptors can modulate retino-collicular transmission and appear to be associated with habituation processes during visual responses in vivo. Taking together functional and anatomical data it is evident that mGlu4, mGlu8 and possibly mGlu7 play a significant role in visual processing in the adult rat SC. It is now well established that glutamate signalling in the brain changes during development (Lujan et al., 2005). In the rat SC, changes in NMDA receptor function in visual transmission occur after eye opening (at P14), into young adulthood (wP30) and into older ages (Binns and Salt, 1998; Mize and Salt, 2003; Pothecary et al., 2005). However, little is known how the function of mGlu receptors might change during development in the SC. As it is known that Group III receptor expression declines into adulthood in several parts of the brain (Bradley et al., 1998; Catania et al., 1994; Elezgarai et al., 1999; Lujan et al., 2005; Simonyi et al., 2000), and as Group III receptors are involved in visual processing in the SC, we thought it of interest to see if there were changes in Group III receptor function with age. Therefore the aim of the present study was to test the hypothesis that the function of Group III receptors in the SC changes with age. To do this we have investigated the effects of the Group III agonist L-AP4 on retinocollicular transmission in SC slices taken from rats at different ages, from at around eye opening at P14 until late adulthood at P180.

2. Methods Pigmented Lister ‘‘hooded’’ rats, aged either P14, P30, P90 or P180-200 were used throughout. Animals were bred in-house, weaned at P21eP23 and housed on a 12-h light/dark cycle with unlimited access to food and

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water. All conditions and all experimental procedures were in accordance with the UK Animals (Scientific Procedures) Act 1986 and associated guidelines, and steps were taken to minimise suffering and to keep the numbers of animals used to a minimum. Animals were deeply anaesthetized with halothane and decapitated. Their brains were then removed rapidly and placed in ice-cold, oxygenated Krebs medium containing (mM): sucrose 202, KCl 2, KH2PO4 1.25, MgSO4 10, CaCl2 0.5, NaHCO3 26, glucose 10. The cerebellum was removed and an angled (ca. 45 degrees to the midline) cut made across the frontal cortex. The block of brain was glued to the cutting stage of a vibratome from which 300 mm slices of the SC were prepared. In this way the integrity of retinal input to the superficial layers of the SC is maintained as it enters the SC. The slices were transferred to oxygenated Krebs medium containing (mM): NaCl 124, KCl 2, KH2PO4 1.25, MgSO4 5, CaCl2 1, NaHCO3 26, glucose 10. After 1 h, a slice was transferred to an interface recording chamber where it was perfused at 33e34  C with Krebs medium containing (mM): NaCl 124, KCl 2, KH2PO4 1.25, MgSO4 1, CaCl2 2, NaHCO3 26, glucose 10. Extracellular recordings were made via Krebs-filled, glass micropipettes (5e10 mm in diameter) positioned in the superficial grey layer of the SC. Stimulation of the retinal input (0.1 ms pulses, 100e500 mA) was via a bipolar tungsten-in-glass electrode positioned in the optic tract outside the SC, approximately 250e600 mm rostral to the recording electrode. Stimulus intensity was adjusted to produce responses 25e30% above threshold. Pairs of stimuli separated by 20 ms were given once every 15 s or 30 s. Responses were recorded with an Axoprobe 1A amplifier (Axon Instruments), filtered with a 5-kHz cut-off, digitised (10 kHz) via a CED micro-1401 interface and stored on a computer with Spike 2 software (Cambridge Electronic Design). Responses to stimuli were waveform-averaged (six trials), and peak amplitude and area-under the curve measurements made, taking the period before the stimulus artefact as the baseline. Agonists and antagonists were applied to the tissue by addition to the bathing medium. L-AP4 was routinely applied for 10 min, and the effect on synaptic responses assessed in the final 2 min of this period. In experiments where involvement of GABAergic mechanism was investigated, the GABA antagonists picrotoxin (100 mM) and CGP55845A (3 mM) were applied together continuously for a least 20 min before investigating the effects of LAP4 under these conditions. Agonist effects on fEPSP amplitude were normalised to amplitude values obtained under baseline conditions. To test statistical significance of L-AP4 effects, the KruskaleWallis test was used, and further tests for significant differences between groups were carried out using the Wilcoxon test.

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3. Results 3.1. Characteristics of synaptic responses Stimulation of the optic tract resulted in a field EPSP (fEPSP) response with characteristics similar to those we have described previously (Cirone et al., 2002a; Pothecary et al., 2002, 2005; Thompson et al., 2004). Responses to a second stimulus (20 ms following the first) were consistently depressed compared to the first (paired-pulse depression; p ! 0.05, Wilcoxon test). Similar results were seen in all of the age groups tested (Fig. 1). 3.2. Effects of L-AP4 on retino-collicular responses Application of L-AP4 (10 mM) resulted in a reduction of the fEPSP amplitude ( p ! 0.05, Wilcoxon test), as described previously by ourselves (Pothecary et al., 2002; Thompson et al., 2004), and increasing the concentration of this agonist to 100 mM resulted in

A

0.2mV

further reductions in EPSP amplitude ( p ! 0.05, Wilcoxon test, Figs. 2 and 3). Increasing the concentration of L-AP4 beyond 100 mM to 500 mM did not have a significantly greater effect, as indicated by the concentrationeresponse curve in Fig. 3. The effects of L-AP4 were relatively rapid in onset (2e3 min from start of application) and were readily reversible upon washout (Fig. 2). The greatest effects of L-AP4 were seen at age P14, when 10 mM and 100 mM agonist concentrations produced fEPSP amplitude reductions of 318.4% and 702.9%, respectively ( p ! 0.05, Wilcoxon test). With increasing age, L-AP4 was progressively less effective, although fEPSP amplitudes were still reduced at the oldest age tested (Fig. 5A). The reduced effectiveness of L-AP4 with increasing age was found to be significant (p ! 0.05, KruskaleWallis test). In view of the possibility that there might also be a GABAergic contribution to the modulatory effects of L-AP4, as suggested by Cirone & Salt on the basis of in vivo data (Cirone and Salt, 2001), the effects of L-AP4 (100 mM) were also investigated in the presence of GABA antagonists. Application of a combination of picrotoxin (100 mM) and CGP55845A (3 mM), which is known to block GABAa, GABAb and GABAc receptors in the SC (Boller and Schmidt, 2001; Bormann, 2000), resulted in a prolongation of fEPSPs but not an increase in peak amplitude, as might be expected (Cirone et al., 2002a; Pothecary et al., 2005). Under these conditions, at all ages, L-AP4 (100 mM) was found to have similar effects in reducing fEPSP amplitude ( p ! 0.05, Wilcoxon test) as it did in normal medium (Figs. 4 and 5). Similarly, there was a significant reduction in the effectiveness of L-AP4 with age (p ! 0.05, KruskaleWallis test, Fig. 5).

10ms OT

OT

3.3. Effects of L-AP4 on paired-pulse depression

B EPSP2/EPSP1 (%)

100 80 60 40 20 0 P14

P30

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Fig. 1. (A) Waveform-averaged (n Z 6) fEPSP response to two stimuli given to the optic tract at the times indicated by the markers (OT) from a rat aged P14. Note the reduction of the second response (EPSP2, arrow) compared to the first response (EPSP1). (B) Average (Gs.e.m.) paired-pulse ratio for rats of different ages. The paired-pulse ratio is expressed as the percentage of EPSP2 compared to EPSP1. Note that the paired-pulse ratio does not change with age.

Both 10 mM and 100 mM L-AP4 consistently reduced fEPSP responses to the first stimulus of a pair more than they did the second (Fig. 6; p ! 0.05, Wilcoxon test). Overall, this paired-pulse depression was reduced when 10 mM L-AP4 was applied, and it is noteworthy that at this concentration of agonist fEPSP1 was significantly reduced whereas fEPSP2 was not. Application of 100 mM L-AP4 always had a larger effect than 10 mM ( p ! 0.05, Wilcoxon test). When 100 mM L-AP4 was applied, the paired-pulse depression was converted to a paired-pulse potentiation, but this could be attributed to a significant reduction of fEPSP2 under these conditions (p ! 0.05, Wilcoxon test). Similar effects were seen at all ages, although the agonist did appear to have more pronounced effects on paired-pulse depression in the younger age groups (P14, P30) than in older animals (Fig. 6).

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A Control

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Fig. 2. (A) Waveform-averaged fEPSP responses to optic tract stimulation (OT), under control conditions and during the application of L-AP4 at concentrations of either 10 mM or 100 mM, and upon washout of the agonist from the bath. Note the depressions of fEPSP during agonist application. Data taken from a rat aged P14. (B) Time course of L-AP4 effects, from the same experiment as in A. The plot shows the fEPSP amplitude (average of six individual responses) as a percentage of control. Timing of L-AP4 applications is indicated by the bars. Note the greater effect of AP4 100 mm compared to AP4 10 mm. (C) Time course of L-AP4 effects, averaged from five experiments in slices from P14 rats. The plot shows the average fEPSP amplitude (Gs.e.m.) as a percentage of control. Timing of L-AP4 applications is indicated by the bars.

4. Discussion 4.1. Activation of Group III receptors in the SC by L-AP4

% reduction of peak

60 50 40 30 20 10 0 1

10 L-AP4 (µM)

100

Fig. 3. Concentrationeresponse curve for L-AP4 effect on fEPSP amplitude. Values are means G standard error of mean. Dashed line shows non-linear fit to sigmoidal curve.

The results presented here indicate that activation of Group III mGlu receptors has a powerful effect in reducing retino-collicular transmission in the rat. This is consistent with previous in vivo and in vitro work from this laboratory (Cirone and Salt, 2001; Pothecary et al., 2002; Thompson et al., 2004), as well as with previous binding studies (Thomsen and Hampson, 1999). Our previous findings that L-AP4 effects in the SC in vivo or in vitro are antagonised by the antagonists (RS )-cyclopropyl-4-phosphono-phenylglycine (CPPG) and (RS )methyl-4- phosphono-phenylglycine (MPPG) (Cirone and Salt, 2001; Thompson et al., 2004) indicate that the effects seen with L-AP4 are indeed mediated via Group III mGlu receptors. The lower concentration of the Group III mGlu receptor agonist L-AP4 (10 mM) used in the present study would be appropriate to activate mGlu4 and mGlu8 receptors maximally, but not mGlu7 receptors whereas the higher concentration (100 mM) would activate all of these Group III receptors (Schoepp

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A

Control (Pic & CGP)

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140 120 100 80 60 40 20 0 0

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Fig. 4. (A) Waveform-averaged fEPSP responses to optic tract stimulation (OT) during the continuous application of picrotoxin and CGP55845A, showing the effect of application of L-AP4 (100 mM). Data taken from a rat aged P14. (B) Time course of L-AP4 effects, from the same experiment as in A. The plot shows the fEPSP amplitude (average of six individual responses) as a percentage of control. (C) Time course of L-AP4 effects, averaged from five experiments in slices from P14 rats. The plot shows the average fEPSP amplitude (Gs.e.m.) as a percentage of control.

et al., 1999; Thomsen and Hampson, 1999; Valenti et al., 2003). Our finding that 100 mM L-AP4 had a substantially greater effect on fEPSP responses than 10 mM L-AP4 would therefore suggest that there are functional mGlu7 receptors in the SC in addition to functional mGlu4 and mGlu8 receptors. A contribution from the other Group III receptor, mGlu6, appears unlikely, as this receptor is restricted largely to retinal biopolar cells (Nakajima et al., 1993). Our data obtained with L-AP4 are also consistent with neuroanatomical data at the light- and electronmicroscopic level (Cirone et al., 2002b; Puente et al., 2005). All three Group III mGlu receptors have been demonstrated in the superficial SC by immunohistochemistry and in situ hybridisation. In particular, mGlu4 receptor protein is located on the identified terminals of the excitatory cortical and retinal afferents in the superficial layers of the rat SC (Puente et al., 2005). Although similar studies have not yet been attempted for mGlu7 and mGlu8, mRNA and protein for mGlu7 (Bradley et al., 1998; Hartveit et al., 1995; Kinoshita et al., 1998; Ohishi et al., 1995; Tehrani et al., 2000) and mGlu8 (Duvoisin et al., 1995; Koulen et al.,

1999; Saugstad et al., 1997; Tehrani et al., 2000) have been found in brain areas that project to the SC. Thus it is possible that there is a contribution from mGlu7 and mGlu8 receptors to the effects seen with L-AP4 in the present study. Indeed, functional studies from this laboratory (Pothecary et al., 2002) indicate that mGlu8 receptors are involved in modulating retino-collicular transmission, although binding studies suggest that mGlu4 receptors account for a large majority of LAP4-sensitive Group III receptors in the SC (Thomsen and Hampson, 1999). 4.2. Possible relationship of mGlu function with GABAergic transmission The mammalian SC is a complex structure which contains one of the highest densities of GABA-containing neural elements in the brain (Mize, 1996). It is known that synaptic inputs to this structure, both in vivo and in vitro, activate GABAergic circuitry leading to inhibitory synaptic response components (Binns and Salt, 1997; Boller and Schmidt, 2001; Edwards et al., 2002; Mize and Salt, 2004; Pasternack et al., 1999).

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A

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40 30 20 10

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0 L-AP4 10µM

L-AP4 100µM

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Fig. 5. (A) Average effect of L-AP4 (10 mM and 100 mM) (expressed as mean reduction of fEPSP amplitude) in rats of different age groups. Note that L-AP4 had a greater effect in younger rats. (B) Average effect of L-AP4 (100 mM) in the presence of picrotoxin and CGP55845A in rats of different age groups. Note that L-AP4 had a greater effect in younger rats. *Significant difference from control (p ! 0.05).

Furthermore, we have previously suggested, on the basis of in vivo experiments, that L-AP4 may in some circumstances exert a modulatory function on SC visual responses via an interaction with GABAergic inhibition (Cirone and Salt, 2001). In order to evaluate the potential contribution of GABAergic mechanisms to the effects of L-AP4 in the present experiments, we carried out some experiments where all three of the GABA receptors that are present in the rat SC (GABAa, GABAb, GABAc) were blocked with a combination of picrotoxin and CGP55845A (Boller and Schmidt, 2001; Bormann, 2000). Under these conditions, L-AP4 produced a similar effect on fEPSPs as it did under control conditions: this indicates that GABAergic mechanisms do not contribute to the modulation of retino-collicular transmission by Group III mGlu receptors. This would be consistent with ultrastructural evidence that, in the SC, mGlu4 receptors are not associated with GABAergic neural elements (Puente et al., 2005). However, this does not preclude the indirect involvement of GABA receptors in the modulation of visual responses in vivo, as it is probable that Group III receptors modulate excitatory input onto GABAergic neurones that contribute to the overall visual response of SC neurones (Cirone and Salt, 2001).

1999; Conn and Pin, 1997; Schoepp, 2001). It is not possible to exclude a post-synaptic effect of L-AP4 on SC neurones on the basis of the present data, but it is noteworthy that we have previously shown that L-AP4 does not reduce SC neurone responses to ionotropic glutamate receptor agonists in vivo (Cirone and Salt, 2000). Furthermore, ultrastructural studies have demonstrated mGlu4 receptors on excitatory afferents to the superficial SC rather than on post-synaptic elements (Puente et al., 2005). This correspondence of agonist effect with presynaptic localisation of mGlu4 receptors lends further support to the hypothesis that mGlu4 receptors make a major contribution to the effects on transmission in the SC seen with L-AP4. It is also interesting to note that fEPSP responses, especially fEPSP1, often appeared to have several components (e.g. Fig. 1). This may reflect heterogeneity of inputs to the SC or activity within local circuits, and it is possible that only some of these elements are affected by L-AP4. More detailed information on the location of mGlu7 and mGlu8 would be of value in interpreting these data, but the subcellular location of mGlu7 and mGlu8 in the SC is still unknown, although these receptors have been found at presynaptic locations in other brain areas (Kinoshita et al., 1996; Ohishi et al., 1996; Shigemoto et al., 1996).

4.3. Effect of L-AP4 on paired-pulse depression 4.4. Age-related functional changes A consistent finding of the present study was that LAP4 reduced the first fEPSP of a pair more than it did the second, and thus that paired-pulse depression was reduced. This is consistent with the idea that L-AP4 reduces synaptic transmission via presynaptic receptors, a mechanism that has been demonstrated for Group III receptors in several other parts of the brain (Anwyl,

The results presented here are to our knowledge the first functional demonstration of a change in role of Group III receptors in synaptic modulation over this age range in any part of the brain. Our finding that the effectiveness of L-AP4 declines between P14 and P180 is in accord with information that indicates a decline in

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A Control

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160

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Fig. 6. (A) Waveform-averaged fEPSP responses to paired optic tract stimulation (OT), under control conditions and during the application of L-AP4 at concentrations of either 10 mM or 100 mM. Note the greater reduction of EPSP1 compared to EPSP2 at both agonist concentrations. (B) Average paired-pulse ratios (as a percentage) under control conditions, during 10 mM L-AP4 and upon washout of agonist, taken from rats of different ages. Note the greater effect of L-AP4 on the paired-pulse ratio in younger animals. *Significant difference from control (p ! 0.05). (C) Similar plots as in B, but showing the effects of 100 mM L-AP4.

mGlu4 and mGlu7 receptors in several brain areas (Bradley et al., 1998; Catania et al., 1994; Simonyi et al., 2000). Unfortunately, there is no specific information concerning the developmental profile of Group III receptors in the SC, but it would seem unlikely that this area of the brain would be substantially different from all the others that have been investigated. Furthermore, the major sources of excitatory input to the superficial SC, retinal ganglion cells and layer 5 cortical cells, show a decline in mGlu4 mRNA and mGlu7 mRNA and protein with age (Bradley et al., 1998; Tehrani et al., 2000). Little is known about the developmental changes in mGlu8 expression, although it appears that the amount of this receptor mRNA that is expressed in retinal ganglion cells does not change between P14 and P60 (Tehrani et al., 2000). It is also noteworthy that the paired-pulse depression under control conditions was similar at all ages in the present study, indicating that the underlying properties of synaptic transmission do not undergo great changes over the P14eP180 age range. This is consistent with the

fact that the retino-collicular pathway is largely mature by P15 (Mize and Salt, 2003), and that after this time point there is further maturation of the corticocollicular pathway into the SC.

5. Conclusions Taken together with previous work from this laboratory and that of others, our results provide new information concerning two major aspects of mGlu receptor function in the SC. Firstly, our results indicate that the Group III receptors mGlu4, mGlu8 and mGlu7 all contribute to the modulation of excitatory transmission to the superficial layers of the SC, but do not appear to directly affect GABAergic transmission in this brain area. The functional significance of this receptor diversity remains unclear at present. Secondly, Group III receptor mediated modulation of excitatory transmission declines with age following eye opening (P14) and progresses into advanced adulthood (P180). This

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might suggest that these receptors have a role in the developmental plasticity which occurs between P14 and P30 (Mize and Salt, 2003) and in normal synaptic function in adulthood.

Acknowledgements This work was supported by the Wellcome Trust.

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