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Journal of Physiology (2001), 534.1, pp. 169-178
© Copyright 2001 The Physiological Society
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ABSTRACT |
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INTRODUCTION |
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Neurones in the superior colliculus (SC) respond to novel environmental stimuli and generate appropriate behavioural and avoidance responses to these novel sensory events (Sparks & Nelson, 1987). In the superficial layers of the SC (SSC), neurones respond exclusively to visual events whilst most neurones in intermediate and deep layers are 'multimodal' and are additionally responsive to auditory and somatosensory stimuli (Sparks & Nelson, 1987). It is critically important that neurones in the SC are able to distinguish between novel and persistent stimuli. To this end, neurones in the SSC 'habituate', producing a strong response to an initial visual stimulus, with subsequent presentations of the stimulus at short intervals causing a decline in the response (Oyster & Takahashi, 1975; Stein, 1984; Sparks & Nelson, 1987). The transmitter mediating visual input to the SSC is likely to be L-glutamate, acting upon ionotropic receptors to produce an excitatory response (Roberts et al. 1991; Binns & Salt, 1994). However, metabotropic glutamate (mGlu) receptors are also present in the SSC and can modulate visual responses (Cirone & Salt, 2000). There are eight known mGlu receptors (mGlu1-mGlu8) and these can be divided into three groups based on sequence homology, pharmacology and coupling to second messenger pathways (Nakanishi, 1992; Conn & Pin, 1997). Studies in various brain regions have shown that Group I (mGlu1 and mGlu5) receptors, which are predominantly coupled to postsynaptic inositol phosphate metabolism, participate in physiological processes such as learning and memory, motor control, and nociception (Conn & Pin, 1997). In contrast, the Group II (mGlu2 and mGlu3) and Group III (mGlu4 and mGlu6-mGlu8) receptors are predominantly coupled to an inhibitory cyclic AMP cascade and have been suggested to be presynaptic receptors in many brain areas (Conn & Pin, 1997). However, the physiological role(s) of Group II and III receptors are less clear than that of Group I receptors, although it has been suggested from in vitro studies that they may be activated by glutamate 'spillover' during periods of intense synaptic activity so as to reduce synaptic transmission (Scanziani et al. 1997; Rusakov & Kullmann, 1998; Mitchell & Silver, 2000). Furthermore, it is unclear whether distinct functional roles can be ascribed to these different receptor groups. In the current study we have explored the physiological and functional roles of Group II and III mGlu receptors in different aspects of visual response processing. Firstly, we have investigated the possibility that activation of mGlu receptors by endogenous glutamate is enhanced during high contrast visual stimuli so as to down-regulate visual responses. Secondly, we have investigated a possible role for Group II and III receptors in the generation of response habituation.
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METHODS |
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Surgery, recording and iontophoresis
All animal experiments were carried out in accordance with the UK Animals (Scientific Procedures) Act 1986 and associated guidelines. Extracellular recordings of action potentials were made from single SSC neurones using multi-barrelled glass iontophoretic micropipettes in adult Lister Hooded rats anaesthetised with urethane (1.25 g kg-1 I.P.) (Binns & Salt, 1997). The pipettes were inserted into the SC via a craniotomy, as detailed by Binns & Salt (1997). The pipette barrels contained a selection of the following solutions: L-2-amino-4-phosphonobutyric acid (L-AP4, pH 7.5), LY354740 (pH 8.5), LY341495 (pH 8.5), (R,S)-
-methyl-4-phosphono-phenylglycine (MPPG, pH 8.5), (R,S)--cyclopropyl-4-phosphonophenylglycine (CPPG, pH 8.5) (all 25 mM in H2O), CGP35348 (10 mM in H2O, pH 3), 100 mM NaCl, 1 M NaCl for current balancing, 4 M NaCl for extracellular recording, and Pontamine Sky Blue to mark recording sites. All drugs were held in the barrels with small positive retaining currents (8-15 nA) and ejected as anions, with the exception of CGP35348 which was retained with a negative current and ejected as a cation. Action potentials were gated with a waveform discriminator and timed and recorded using a CED 1401 computer interface and VS software (Cambridge Electronic Design, UK) which generated peri-stimulus time histograms (PSTHs). At the end of the experiment the rat was killed with an overdose of urethane.
Visual stimuli
A cathode ray tube (CRT; Tektronix) was used to display visual stimuli created by a Picasso visual stimulus generator under computer control. The CRT was located in the receptive field of the neurone, 15 cm away from the left eye of the subject. Non-habituating stimulus cycles consisted of 10 presentations of light bars (luminance either 20 or 12.2 cd m-2) on a dark background (3.1 cd m-2), 5 
10-15 deg moving at 22.5 deg s-1 for 4 s every 10 s. For the habituating stimulus - to reliably induce response habituation - a stimulus moving for 2 s with a 0.5 s interval between each of five presentations was used. This sequence was presented for five trials with an intertrial interval of 10 s. This protocol is similar to one previously shown to be effective in revealing habituation by Binns & Salt (1997). The moving bars were of preferred orientation and direction.
Experimental protocol
Control cycles of visual stimuli to evoke reproducible responses were established before presentation of two or three cycles during continuous ejection of the substance under investigation. Recovery data were then obtained, before collection of new control data and further drug applications. To determine if the Group II antagonist LY341495 could block the effect of either the Group II agonist LY354740 or the Group III agonist L-AP4, the antagonist was continuously ejected for three cycles before an agonist was co-ejected with the antagonist for three cycles. Agonist/antagonist ejection then ceased and recovery data were then obtained. Similarly, to investigate the effect of the GABAB antagonist CGP35348 upon modulation of habituation by Group III agonists or antagonists, CGP35348 was continuously ejected for two or three cycles before Group III compounds were co-ejected with CGP35348 for two cycles. Group III agonist/antagonist ejection then ceased whilst CGP35348 was ejected for a further two cycles. Recovery data were then obtained.
Data analysis
Responses were quantified as counts of action potentials evoked by visual stimuli during presentation of the visual stimulus. The degree of response habituation (Binns & Salt, 1997) was assessed by expressing the response evoked by the fifth presentation of a set of five repeated stimulus presentations as a percentage of the response evoked by the first, using the formula: Habituation = [1 - (response to fifth presentation/response to first presentation)] 100. Data were observed on-line during collection and analysed off-line using Spike2 or VS software (Cambridge Electronic Design). The effect of a test drug is expressed as percentage mean of control cycles of visual responses (or continuous LY341495 or CGP35348 ejection). The Wilcoxon signed-rank test was used to test for significant differences between control data and data obtained during drug applications. All results are expressed as a percentage of control ± S.E.M.
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RESULTS |
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Activation of Group II and Group III mGlu receptors during visual responses
Recordings were made from 52 neurones in 32 rats. In order to investigate the function of Group II mGlu receptors, we used the group-selective agonist LY354740 and antagonist LY341495 as tools (Kingston et al. 1998; Monn et al. 1999). Application of the Group II agonist (-25 to -75 nA iontophoresis current) caused either reversible inhibition or potentiation of visual responses of SSC neurones. In 53 % of 43 cells the agonist caused a facilitation of visual responses (to 140 ± 4.7 % of control) whereas it produced inhibition of visual responses in the remainder (to 74 ± 8.6 % of control) (Fig. 1). The Group II antagonist (-25 to -50 nA) was able to antagonise the effects of the agonist when the two compounds were co-applied (Table 1). Furthermore, when applied alone, the antagonist (-25 to -75 nA) had the opposite effect to the agonist both in cells where the agonist caused inhibition or potentiation of visual responses (responses enhanced to 124 ± 3.5 % of control, and reduced to 74 ± 4.1 % of control, respectively; Fig. 1). This indicates that Group II receptors are activated by an endogenous ligand during visual stimulation. These results are qualitatively similar to those we have previously reported (Cirone & Salt, 2000) using the selective Group III agonist L-AP4 and Group III antagonists CPPG and MPPG (Bedingfield et al. 1996; Toms et al. 1996), thus indicating that there is activation of both Group II and Group III mGlu receptors during these visual responses. Furthermore, the actions of L-AP4 and LY354740 were studied on the same neurone in 22 cases. The distribution of Group II and Group III agonist effects in terms of numbers of cells showing an agonist effect as a percentage of control is shown in Fig. 2. It is evident that the neurones which were inhibited by either agonist form a distinct population from the neurones where visual responses were facilitated, rather than being a single population distributed around 100 % of control. However, analysis of recording depth within the SSC and rostrocaudal or medio-lateral location did not reveal any correlation with agonist effect.
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Figure 1. Modulation of visual responses by Group II receptors A, peristimulus time histogram (PSTH) records from an individual neurone showing that the Group II agonist LY354740 (a) and antagonist LY341495 (b) have the opposite effect in the same neurone. In this neurone, LY354740 has a facilitatory effect, whilst LY341495 causes an inhibition of visual responses. B, data from a different neurone (compare with A) where LY354740 (a) inhibits the visual responses and LY341495 (b) causes a facilitation. The histograms show cumulative counts of action potential spikes (i) under control conditions, (ii) during LY354740 or LY341495 ejection, (iii) recovery data obtained 120 s after drug ejection ceased. Stimulus details: presentation of ten visual stimuli (5 | ||
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Figure 2. Summary of the effects of Group II and Group III receptor activation Histograms showing the distribution of effect of the Group II agonist LY354740 (A) and the Group III agonist L-AP4 (B) amongst SSC neurones. Data from Cirone & Salt (2000) have been included in B, together with new data reported for the first time in the present study. | ||
As the Group II antagonist LY341495 may also have some antagonist activity at Group III receptors (Kingston et al. 1998), we tested its effect against L-AP4. L-AP4 (-50 nA) was still able to produce an effect during the continuous ejection of LY341495 (Fig. 3, Table 1), indicating that LY341495 has Group II selectivity in this study. This indicates that Group II and Group III receptors have distinct and separate actions in this brain area.
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Figure 3. Selective effects of the Group II antagonist LY341495 Data from a single neurone showing that LY341495 blocks the effect on visual responses of LY354740 but not the effect of L-AP4, and therefore has a specific effect upon Group II mGluRs. For details of stimuli and histograms see Fig. 1. a and b, reduction of visual responses by LY354740. c, recovery from the effects of LY354740. d-f, reversible enhancement of visual responses and antagonism of LY354740 by LY341495. g, recovery from the effects of LY341495. h-j, reversible reduction of visual responses by L-AP4. k-m, enhancement of visual responses by LY341495, but lack of antagonism of the L-AP4 effect. n, recovery from the effects of LY341495. | ||
The effect of Group II antagonists varies with visual response magnitude
As previous in vitro work from other brain areas has shown that activation of mGlu receptors occurs under conditions of intense synaptic activation (Scanziani et al. 1997; Rusakov & Kullmann, 1998; Mitchell & Silver, 2000), we probed whether activation of Group II or III mGlu receptors is dependent upon the degree of synaptic input by varying the contrast between the visual stimulus foreground and background. Reduction of contrast resulted in a visual response which was on average 41 ± 4.4 % of the response under normal full contrast. At low contrast, the effects of the Group II antagonist were less prominent than under high contrast conditions, irrespective of whether the antagonist inhibited or reduced visual responses (Table 2, Fig. 4). However, when Group III antagonists (MPPG or CPPG, -25 to -75 nA) were applied, little difference in effect was seen between high and low contrast stimulus conditions (Table 2, Fig. 4).
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Figure 4. Variation of stimulus contrast alters the effect of the Group II antagonist Data from two different neurones showing that the magnitude of effect at low and high stimulus contrast is different for the Group II antagonist LY341495, but not the Group III antagonist CPPG. See Fig. 1 for stimulus details. A, CPPG produces a similar effect on visual responses under conditions of either low stimulus contrast (a) or of high stimulus contrast (b). B, LY341495 has a greater effect on the visual response under conditions of high stimulus contrast (b) than it does under conditions of low contrast (a). | ||
Group III mGluRs and visual response habituation
In order to investigate the possible involvement of mGlu receptors in response habituation, we used the selective agonists and antagonists in experiments with a visual stimulation protocol which resulted in response habituation (that is five single stimuli presented at 0.5 s intervals, Binns & Salt, 1997). Under such conditions, the response to the last stimulus was typically about 42 ± 3.9 % less than the response to the first stimulus. The average extent of habituation observed using the full contrast stimuli was not significantly different from that observed in the same cells using the lower contrast stimuli. The Group III agonist L-AP4 produced an increase in the magnitude of response habituation in cells where L-AP4 inhibited the visual response (Fig. 5) whereas application of the Group III antagonists MPPG or CPPG decreased the extent of response habituation in these same cells (Table 3). In contrast, the Group II agonist (LY354740) and Group II antagonist (LY341495) did not have any such effect upon the extent of response habituation (Table 3). As GABAB (but not GABAA) receptors are also involved in the generation of response habituation in the SSC (Binns & Salt, 1997), we also examined the effect upon response habituation produced by the Group III agonist and antagonist in the presence of the GABAB antagonist CGP35348. The GABAB antagonist, ejected alone (+25 to +100 nA), caused a reduction in response habituation by 16.3 ± 3.4 %, consistent with GABAB antagonism, as described previously (Binns & Salt, 1997). In the presence of the GABAB antagonist, L-AP4 still increased the extent of habituation (Table 3; Fig. 5), whilst MPPG reduced the extent of habituation (Table 3). Taken together, these data suggest that Group III receptors specifically take part in the mechanism of response habituation, and that this is independent of GABAB receptors.
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Figure 5. Activation of Group III receptors modulates response habituation PSTH records from a single neurone showing the effects of L-AP4 on response habituation in the absence and presence of CGP35348. The histograms show counts of spikes evoked by five presentations of identical stimuli (5 | ||
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DISCUSSION |
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The present study has demonstrated that activation of Group II mGlu receptors using LY354740 can produce either inhibitory or facilitatory effects on visual responses in the SSC. This is reminiscent of our previous findings with the Group III agonist L-AP4 (Cirone & Salt, 2000), and this shows that both of these receptor types can influence visual processing in the SSC. Furthermore, our findings that antagonists of Group II and Group III receptors influence visual responses in the opposite direction to the respective agonists on a given neurone indicate that these receptors can be activated by an endogenous ligand during visual synaptic transmission. It is now well established that Group II and Group III mGlu receptors are involved in pre-synaptic inhibition of neurotransmitter release at many central synapses (Forsythe & Clements, 1990; Calabresi et al. 1992; Hayashi et al. 1993; Salt & Eaton, 1995; Conn & Pin, 1997). These actions can include inhibition of the release of glutamate itself, or inhibition of the release of the inhibitory amino acid GABA. Previous work from this laboratory has shown that both glutamatergic excitatory and GABAergic inhibitory processes participate in visual responses in the SC (Roberts et al. 1991; Binns & Salt, 1994, 1997). It is therefore plausible that the inhibitory effects on visual responses of the Group II and Group III agonists are due to presynaptic inhibition of glutamate release, whereas the facilitatory effects of these agonists could be via the reduction of GABAergic transmission (either directly or by reduction of excitatory input to interneurones). It is likely that iontophoretic application of mGlu agonists in the SSC can produce both inhibitory and excitatory effects due to differences in the spatial arrangement of different cell types in relation to the point source of exogenous drug. Furthermore, in a physiological context, the effect of mGlu receptor activation will also depend upon the spatial relationship of receptors with respect to the site of transmitter release.
Although at first sight it appears that activation of Group II receptors has a similar effect on visual responses of SSC neurones as activation of Group III receptors, it is evident from our data that there are clear differences between these two receptor classes. In the present study, we have found that Group III but not Group II receptors modulate habituation of visual responses. Furthermore, we found that the magnitude of Group II antagonist effects on visual responses are dependent upon the degree of visual stimulation, which is not the case when Group III antagonists are used. Such differences are highly suggestive of specific functional roles for these receptors.
The role of Group II receptors
The data with the Group II antagonist show that Group II receptors can be activated by an endogenous ligand during visual stimulation. These receptors are unlikely to be located on retinal axon terminals (Koulen et al. 1996), but expression data reveals mGlu2 and mGlu3 mRNA in all cortical layers (Tanabe et al. 1993; Ohishi et al. 1993a,b) indicating the possibility of functional Group II receptors on cortico-collicular afferents. It is therefore conceivable that the inhibitory actions of Group II agonist are predominantly due to an effect on terminals of cortico-collicular afferents, thus reducing visual responses by inhibiting glutamate release. There is immunohistochemical (Petralia et al. 1996; Kim & Jeon, 1999) and expression data (Ohishi et al. 1993b) indicating the presence of Group II receptors in the SSC. Some of these receptors may be located on interneurones, and it is possible that activation of these receptors could reduce GABAergic transmission (Calabresi et al. 1992; Hayashi et al. 1993; Salt & Eaton, 1995; Cox & Sherman, 1999) thereby causing a facilitation of visual responses. Given the very high level of mGlu3 expression in glia (Ohishi et al. 1993b; Testa et al. 1994; Jeffery et al. 1996; Petralia et al. 1996; Mineff & Valtschanoff, 1999) it is also possible that there is a modulatory effect via receptors on glial cells (Winder & Conn, 1996). Some of these possibilities are indicated in Fig. 6.
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Figure 6 Schematic diagram showing possible locations of Group II and Group III metabotropic glutamate receptors in the SSC, and how they might be activated by glutamate released onto perisynaptic receptors (filled arrows) or by glutamate 'spillover' onto extrasynaptic receptors located away from the release site (dashed arrows). Note that the suggested possibilities are not intended to be exhaustive. | ||
It is noteworthy that the effect of the Group II antagonist changes as stimulus contrast is varied, whereas no such effect is seen with Group III antagonists. There is evidence for the 'extrasynaptic' location of Group II receptors in several brain areas (Nusser et al. 1994; Lujan et al. 1997; Mineff & Valtschanoff, 1999), and it has been proposed that these receptors are only activated when there is 'spill-over' of glutamate out of the main synaptic region, possibly during periods of intense synaptic activity (Scanziani et al. 1997; Rusakov & Kullmann, 1998; Dube & Marshall, 2000; Mitchell & Silver, 2000). Such extrasynaptic receptors could then act either as presynaptic autoreceptors or heterosynaptic receptors to reduce transmitter release, and it would be predicted that an antagonist would have a greater effect under conditions of high synaptic activity (Scanziani et al. 1997; Mitchell & Silver, 2000). However, it has not been clear how relevant this may be to synaptic processing under physiological conditions. Our finding that the effect on visual responses of a Group II antagonist varies with stimulus intensity within the physiological range indicates that the extrasynaptic receptors play a role in synaptic processing during visual responses. It is noteworthy that the contrast-dependent effect of the Group II antagonist was seen both on neurones where the agonist enhanced visual responses or inhibited visual responses. The Group II receptors which might be located on interneurones and glial cells would provide suitable targets in such a mechanism (Fig. 6). Interestingly, for the Group III antagonists, there was no significant difference between their effects at low and high stimulus contrasts. This suggests that the involvement of Group III receptors in synaptic transmission in the SSC is not so dependent upon synaptic concentration of glutamate and could also suggest that Group III receptors have a more 'central' synaptic location (Shigemoto et al. 1996; Ottersen & Landsend, 1997).
The role of Group III mGlu receptors in response habituation
Previous work from this laboratory has shown that GABAB (but not GABAA) receptors contribute to the process of response habituation (Binns & Salt, 1997). In the present study, we have shown that activation of Group III receptors with L-AP4 enhances habituation, whereas habituation is reduced by the Group III antagonist MPPG. There is evidence for high levels of expression of mGlu4 mRNA in retinal ganglion cells (Akazawa et al. 1994; Hartveit et al. 1995), and it is possible that this reflects functional receptors at the terminals in the SC. Other studies suggest that Group III receptors may also be present on the terminals of cortico-collicular afferents (Kinzie et al. 1995; Ohishi et al. 1995) and on intrinsic cells of the SSC (Kinzie et al. 1995; Ohishi et al. 1995; Bradley et al. 1998). As the effects of L-AP4 and MPPG are still evident in the presence of the GABAB antagonist, it seems unlikely that receptors located on GABA interneurones or their input contribute to the modulation of habituation by Group III receptors. Furthermore, in the rabbit response habituation does not appear to depend on cortical input (Horn & Hill, 1966; Stewart et al. 1973), and it is thus possible that habituation arises as glutamate released by retinal afferents activates presynaptic mGlu autoreceptors, down-regulating glutamate release and causing the response to habituate (Fig. 6). However, as we found that the Group III agonist did not occlude response habituation it may be that the Group III receptors in some way modulate the habituation rather than participating directly in it. An additional contributory factor could be an inhibitory postsynaptic action of Group III receptors (Martin et al. 1997; Cirone & Salt, 2000). In contrast, Group II mGlu receptors do not appear to be specifically involved in response habituation, and this is supported by the lack of or low levels of Group II receptors located on the terminals of retinal ganglion cells (Hartveit et al. 1995). Activation of the retinal afferents also provides glutamatergic drive to the GABAergic inhibitory interneurone which produces response habituation in the SSC via GABAB receptors (Binns & Salt, 1997). Thus, response habituation is generated by complementary mGlu and GABAB components.
Conclusions
The SC is critical in the integrative processing of sensory information for the purpose of producing orienting behavioural responses to novel sensory stimuli. The present findings indicate that glutamate is able to produce complex effects, both at the synapse and extrasynaptically, which may depend upon a number of factors including the involvement of both ionotropic and metabotropic receptors, concentration of glutamate at the synapse and extent of transmitter diffusion. In particular, our results show that mGlu receptors are important in shaping the visual response properties of neurones in the SSC, and that Group II and Group III receptors have distinct functional roles. We have shown that Group III mGlu receptors contribute significantly to response habituation, a phenomenon thought to underpin novelty detection. In contrast, Group II mGlu receptors appear to have a distinct role in modulating responses at higher levels of visual stimulation, and this may provide an additional, central, mechanism for adaptation to high contrast stimuli.
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Acknowledgements
This work was supported by the UK Medical Research Council. LY354740 and LY341495 were gifts from Lilly Research. We thank Drs K. E. Binns and J. P. Turner for critical reviews of an early draft of the manuscript and for helpful discussions.
Corresponding author
T. E. Salt: Department of Visual Science, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
Email: t.salt{at}ucl.ac.uk
Author's present address
J. Cirone: Neuroscience Research Centre, Merck Sharpe & Dohme, Terlings Park, Harlow, UK.
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