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1Departments of Neurological Surgery and 2Neuroscience and the 3McKnight Brain Institute, University of Florida; and 4Malcolm Randall Veterans Affairs Medical Center, Gainesville, Florida 32608
Submitted 23 December 2003; accepted in final form 22 March 2004
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ABSTRACT |
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INTRODUCTION |
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; Choi and Lovinger 1997; Pouzat and Hestrin 1997; Reyes and Sakmann 1999). The switch from short-term depression to short-term facilitation and the increase in the failure rate indicate a decrease in release probability in the maturing presynaptic terminal (Pananceau et al. 1998; Stevens and Wang 1995; Thomson 2000). However, the mechanisms that underlie this developmental change in release probability remain to be elucidated.
Metabotropic glutamate receptors (mGluRs) act as powerful regulators of synaptic transmission in the CNS (Anwyl 1999). At resting conditions, a low level of free glutamate exists in the perisynaptic extracellular space (Danbolt 2001). This ambient glutamate could act on some mGluRs because of their high affinity to glutamate (Meldrum 2000). Recently, it was reported that blocking mGluRs enhanced the baseline synaptic response in both glutamatergic and GABAergic synapses in the CNS. This was accompanied by a decrease in paired-pulse facilitation (Bandrowski et al. 2003; Cao et al. 1997; Losonczy et al. 2003; Piet et al. 2003; Schrader and Tosker 1997), implying that tonic activity of presynaptic mGluRs regulates the release probability of synapses. However, the physiological relevance of tonic mGluRs activity in the developing brain has not been explored.
Ambient glutamate concentration is mainly controlled and regulated by glutamate transporter activity and extracellular space (Danbolt 2001). Blockade of glutamate transporters increases ambient glutamate concentration and presynaptically reduces baseline synaptic transmission. This reduction of baseline synaptic transmission is blocked by mGluR antagonists and mimicked by application of glutamate (Kidd and Isaac 2000; Maki et al. 1994; Oliet et al. 2001). The activity of transporters is likely age dependent as the effect of blockade of glutamate transporters on synaptic transmission was not found in the mature slice (Isaacson and Nicoll 1993). This age dependence was further supported by the finding that expression of glutamate transporters in neocortex is regulated developmentally (Furuta et al. 1997). In addition, the extracellular space around the synapse also undergoes developmental changes as it has been reported to be larger in immature brain compared with mature brain (Tashiro et al. 2003; Vaughn 1989).
We hypothesized that the ambient glutamate concentration is subject to developmental regulation and would increase during cortical maturation. Acting via mGluRs, this would result in reduction of release probability during postnatal cortical development. To test this hypothesis, we have studied the effect of modulators of mGluRs and glutamate transporters on glutamatergic synaptic transmission and STP at different stages of postnatal cortical development. We found that tonic activity of mGluRs receptors increased during development, and the increase was, in part, due to a developmental decrease in glutamate transporter activity.
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METHODS |
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). The animal was anesthetized by inhalation of isoflurane and decapitated, and the brain was rapidly removed. Slices (400-µm thick) were cut at the rostrocaudal level of the anterior commissure using a Vibratome (Technical Products International, St. Louis, MO). Slices were incubated on cell culture inserts (8 µm pore diameter, Becton Dickinson, Franklin Lakes, NJ) covered by a thin layer of artificial cerebrospinal fluid (ACSF, see following text) containing 1 mM Ca2+ and 6 mM Mg2+ and surrounded by humidified 95% O2-5% CO2 atmosphere at room temperature (22°C). For recording, a single slice, after 
1 h incubation, was transferred to a submerged recording chamber with continuous flow (2–3 ml/min) of ACSF that contained (in mM) 124 NaCl, 26 NaHCO2, 1.25 NaH2PO4, 2.5 KCl, 2 CaCl2, 1 MgCl2, and 10 D-glucose, gassed with 95% O2-5%CO2 giving pH 7.4. All experiments were carried out at room temperature (22°C).
Whole cell recordings were made from pyramidal neurons in layer of IV/V of neocortex under visual control using infrared differential interference contrast (IR-DIC) videomicroscopy with a fixed-stage microscope (Axioskop-FS; Zeiss, Oberkochen, Germany) equipped with a 40x, 0.8-W water-immersion objective. Patch electrodes had a resistance of 3–5 M
when filled with internal solution containing (in mM) 120 K-gluconate, 8 NaCl, 10 HEPES, 4 MgATP, 0.3 Na3GTP, and 0.2 EGTA (pH = 7.3 with KOH, osmolarity = 290–300 mOsm). Pyramidal neurons were identified by their triangular somata, a single apical dendrite and regular spiking pattern in response to a depolarizing current pulse in current-clamp configuration. Some recorded neurons were further characterized by successful biocytin staining using 0.1% biocytin in the electrode filling solution. Neurons were voltage-clamped at –68 mV using an Axopatch 1D amplifier (Axon Instruments, Foster City, CA). GABAergic input was blocked by adding the GABAA receptor blocker, picrotoxin (50 µM, Sigma, St. Louis, MO) to the bath solution.
To evoke monosynaptic excitatory postsynaptic currents (EPSCs), a glass electrode (3–5 M) filled with ACSF was placed in layer IV/V 50–70 µm away from the cell bodies that were being recorded. Five-pulse trains at 20 Hz were given to elicit EPSCs. The interval between trains was 10 s. Monosynaptic currents were identified by their constant latency and a single peak for all five responses. Stimulation strength was adjusted to induce the first response with an amplitude 
100 pA. For minimum stimulation, the intensity of stimulation was adjusted to have two to three failures in each 5- pulse train. Series resistance (14–25 M) was monitored continuously by applying a hyperpolarizing pulse before each stimulus. The recordings were discarded if a change of series resistance 10% occurred. (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV; Tocris Cookson, Ballwin, MO), L-(+)-2-amino-4-phosphonobutyric acid (L-AP4; Tocris Cookson), L-trans-pyrrolidine-2,4-dicarboxylate (tPDC; Sigma) and dihydrokainate (DHK; Sigma) were first dissolved in water as stock solution and then diluted into bath solution to the desired concentration. 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl) propanoic acid (LY341495; Tocris Cookson) was dissolved in 100% dimethyl sulfoxide (DMSO; Sigma). The final concentration of DMSO in bath solution was <0.01%. At this concentration, DMSO did not affect synaptic transmission. In experiments where tPDC and DHK were used, D-2-amino-5-phophonopentanoic acid (AP5, 50 µM, Tocris Cookson) was added in solution to block N-methyl-D-aspartate (NMDA) receptors. Data were acquired and stored using pClamp 8 (Axon Instruments) and analyzed using Clampfit 8 and Origin 6 software. Short-term plasticity was quantified by normalizing the amplitude of all five responses to that of the first response. All values were expressed as means ± SE. The paired or unpaired Student's two-tailed t-test was used to test the significance of changes. Statistical significance was set at P < 0.05.
Slices containing biocytin-filled cells were kept in 4% paraformaldehyde overnight at 4°C, rinsed in PBS (0.1 M) two times for 30 min, and then incubated in 0.1% ExtraAvidin peroxidase (Sigma) in PBS solution overnight. Slices were treated with 3% H2O2 for 5 min, rinsed with PBS and acetate buffer, and then reacted for 10 min with a solution of 0.5 mg/ml 3.3'-diaminobenzidine (Sigma), 4%Ni-DAB chromagen and 0.2 µl/ml 30% H2O2 in sodium acetate buffer. Slices were then rinsed in sodium acetate buffer, dehydrated, mounted onto slides, and coverslipped.
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RESULTS |
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We performed whole cell recordings from layer IV/V pyramidal neurons and monosynaptic EPSCs were evoked by 5-pulse (20 Hz) train stimulation. In agreement with previous reports (Reyes and Sakmann 1999), we found that STP at the early stage of development (P13–17) consistently showed depression. However, the depression gradually switched to facilitation during the first month of postnatal development. By P28, STP showed facilitation of responses two to five in the train, as illustrated in Fig. 1, A and B. In agreement with previous work (Reyes and Sakmann 1999), our data with minimal stimulation showed an increase in the failure rate during development, which is inversely correlated with short-term depression (data not shown). Because STP is determined largely by presynaptic mechanisms (Pananceau et al. 1998), our results support the idea that the release probability of CNS synapses is downregulated during postnatal development (Bolshakov and Siegelbaum 1995; Choi and Lovinger 1997; Pouzat and Hestrin 1997; Reyes and Sakmann 1999).
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Synaptic transmitter release is strongly regulated by presynaptic mGluRs. Among eight types of mGluR, mGluR2/3 has been extensively studied both in hippocampus and cortex and has been consistently shown to depress synaptic response by reducing release probability (Anwyl 1999; Schoepp 2001). We tested the effect of activation of mGluR2/3 on synaptic transmission using the agonist, DCG-IV, to see if it changed during postnatal development. We found that application of DCG-IV (2–4 µM) reversibly suppressed stimulus-evoked EPSCs at both P13–17 and P28–42 (Fig. 2, A and B). As shown in Fig. 2C, it suppressed the first EPSC to 37% of control in the younger group (n = 9) and to 31% of control (n = 10) in the older group. This effect was not different between the two age groups (P > 0.05). As shown in Fig. 2C, the effect of DCG-IV on EPSC amplitude and STP was completely blocked by LY 341495 (2 µM, n = 5 for P13–17, n = 7 for P28–42). As illustrated in Fig. 2, A and B, DCG-IV produced a conversion of short-term depression into short-term facilitation at the early stage and a further increase in facilitation at the late stage. In an attempt to address issues of specificity between group II and group III mGluRs, we examined the effect of L-AP4, a group-III-specific activator on EPSC amplitude. At P13–17, L-AP4 (50 µM) produced a modest reduction in amplitude of the initial EPSCs (84 ± 3% of pretreatment, n = 11, P < 0.05). A similar effect was seen at P28–42 (87 ± 4% of pretreatment, n = 9, P < 0.05).
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We used a LY341495, an mGluR antagonist that is most potent at mGluR2/3 (Kingston et al. 1998), to test the effect of tonic activity of mGluRs on synaptic transmission and STP. LY341495 (2 µM) rapidly, reversibly, and significantly enhanced the amplitude of evoked EPSCs in most of cells recorded at the late stage (P28–42), although the magnitude of the enhancement varied from cell to cell (Fig. 3B). On average, the amplitude of the first EPSC was enhanced by 31% (n = 17, P < 0.05; Fig. 3I). This enhancement was accompanied by a significant decrease in short-term facilitation (Fig. 3, C and G), with some cells even converting from facilitation to depression, indicating an increase in release probability. The decrease of short-term facilitation was inversely correlated with the enhancement of the first EPSC (Fig. 3H). However, LY341495 had no significant effect on either EPSC amplitude or STP at the early stage (P13–17), as shown in Fig. 3, D–F. On average, the amplitude of the first EPSC at P13–17 was 101% of control after LY341495 (n = 14; Fig. 3I). These results indicated that the effect of LY341495 was age dependent. We then examined the effect LY431495 on EPSCs at an intermediate age (P19–P25). As shown in Fig. 3I, at P19–25, LY 341495 had a relatively small but significant effect. On average, it enhanced the first EPSC amplitude to 114% of control (n = 13, P < 0.05). These results indicated that there is a progressive increase in tonic activity of mGluRs during development.
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Tonic activity of mGluRs is maintained by ambient glutamate in the extracellular space. Our results suggested that ambient glutamate levels might be higher in the more mature animals (P28–42) than in the immature group (P13–17). Two major factors regulate the ambient glutamate concentration: glutamate transporters and the size of the extracellular space (Danbolt 2001). We tested a possible role for glutamate transporters using the glutamate transporter inhibitor, tPDC. tPDC is a potent, but nonspecific, inhibitor of both glial and neuronal glutamate transporters (Bridges et al. 1991). As shown in Fig. 4, A–D, tPDC (300 µM) significantly decreased the amplitude of the first EPSC and reduced short-term depression at P13–17 (13 of 16 neurons). The average amplitude of the first EPSC was depressed to 73% of control (n = 16, P < 0.05; Fig. 4F). The reduction of short-term depression was negatively correlated with the change in amplitude of the first EPSC (r = –0.88), as shown in Fig. 4E. However, tPDC had no effect on EPSC amplitude and short-term facilitation at P28–42. After application of tPDC, the average amplitude of the first EPSC was 103% of control (n = 12, P > 0.05; Fig. 4F). These data indicated that the effect of tPDC was also age dependent. We then tested its effect in an intermediate age group (P21-25). It turned out that the effect was widely variable. On average, the amplitude of the first EPSC was 96% of control after tPDC, not significantly different from controls (n = 11, P > 0.05; Fig. 4F).
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). We thus tested the combination of DHK (100 µM) and tPDC (300 µM) at P13–17 and P28–42. However, in our hands, this combination did not produce an additive effect. Rather, the combination of DHK and tPDC increased the holding current, making the recording unstable. The increase in holding current was not likely due to activation of NMDA receptors resulting from increased ambient glutamate levels because the effect persisted in the presence of AP5 (50 µM). Instead, we found, in current-clamp configuration, that application of DHK gave rise to a large depolarization of the membrane potential (data not shown). DHK has been reported to act directly on 
-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (Bridges et al. 1991; Maki et al. 1994). Therefore this effect on the membrane potential might reflect the activation of postsynaptic AMPA receptors. The effect of application of tPDC on synaptic transmission was completely abolished in the presence of LY341495 (Fig. 4F), indicating that tPDC reduced synaptic transmission by activation of mGluR receptors. Although tPDC decreased EPSC amplitude and reduced short-term depression at P13–17; in most cases, it did not convert this response to the short-term facilitation that is seen at P28–42. This suggests that alterations in glutamate transporters are not the only factor regulating ambient glutamate and STP during postnatal cortical development.
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DISCUSSION |
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Previous immunocytochemical and morphological data add support to the proposition that ambient glutamate levels may rise during postnatal neocortical development. Glutamate transporters and size of the extracellular space are major factors controlling the concentration of ambient glutamate (Danbolt 2001). Both of them appear to undergo developmental changes. It has been reported, in rat cortex, that expression of the neuronal glutamate transporter reaches a maximum at P5-16, then decreases with further maturation (Furuta et al. 1997). In addition, extracellular space around the synapses is much larger in immature cortex compared with mature cortex, thus promoting diffusion of glutamate (Tashiro et al. 2003; Vaughn 1989). Smaller extracellular space and more complex structures around synapses in mature cortex constrain the free diffusion of glutamate and this would promote higher ambient glutamate concentrations around presynaptic terminal. The sensitivity and density of presynaptic mGluRs may also affect the tonic activity of mGluRs. However, it is not clear if the sensitivity and density of mGluRs also undergo developmental modification. Our current result, that an agonist of mGluR2/3 (DCG-IV), in the same concentration, depressed stimulus-evoked EPSCs to a similar extent at P13–17 and P28–42, suggests that changes in sensitivity or density of mGluRs might not account for our findings. But we cannot rule out this possibility based on our current data.
It appears that the activity of presynaptic mGluRs differentially regulates synaptic transmission under different physiological conditions with different demands. When synapses are intensively stimulated, presynaptic mGluRs receptors can respond to the increase of glutamate in the synaptic cleft and act to prevent excessive increases in excitation (Scanziani et al. 1997). On the other hand, under resting conditions, mGluRs can be tonically activated by ambient glutamate, which may play an important role in setting the initial release probability of cortical synapses. Different types of mGluRs have distinct localization within the presynaptic terminal, indicating each type might have distinct functional roles (Cartmell and Schoepp 2000; Lujan et al. 1997). mGluR2/3s are localized to the preterminal axons and have a higher affinity for glutamate than most other mGluRs (Meldrum 2000). Thus mGluR2/3 may be better suited to sense low ambient glutamate levels and regulate initial release probability.
Our present results indicate that tonic activity of mGluRs is subject to developmental regulation. This could help reconcile perceived inconsistencies in previous studies that did not find tonic activity of mGluRs (Kidd et al. 2002; Scanziani et al. 1997) due to the fact that, in those studies, immature animals were used. It appears that the maturation of CNS synapses is characterized by a progressive lowering of release probability. It may be that higher release probabilities provide an important trophic effect in immature cortex where synapse formation is important. Conversely, low release probabilities in mature cortex may confer a wider dynamic range on the synapses, thus promoting functional plasticity, and help in stabilizing the neural network.
In any pharmacological study, issues of specificity are important to consider when interpreting results. Although it is most potent at mGluR2/3, LY341495 at a concentration of 2 µM likely blocks the group III mGluRs, mGluR6-8, as well (Kingston et al. 1998). However, it has been reported that mGluR6 is confined almost entirely to the retina (Nakajima et al. 1993). mGluR7 is highly expressed in cerebral cortex and localized in active zones of presynaptic terminal (Bradley et al. 1998), But glutamate has a low affinity at mGluR7 (EC50 > 0.5 mM); thus at resting conditions, it may not be activated by ambient glutamate concentrations of 0.5–2 µM (Cartmell and Schoepp 2000; Meldrum 2000). mGluR8 is highly expressed in the olfactory bulb and, to a lesser extent, in the cerebral cortex (Duvoisin et al. 1995). Similar to mGluR2/3, mGluR8 has a high affinity for glutamate and may also be localized in presynaptic terminals (Schoepp 2001). Therefore it is possible that presynaptic mGluR8 is tonically activated at resting conditions and plays a role in reducing transmitter release probability. However, we observed that L-AP4, a group III mGluR-specific agonist at 50 µM, only slightly reduced evoked-EPSC amplitude. At this concentration of L-AP4, mGluR8s should be maximally activated (Cartmell and Schoepp 2000). Therefore we feel that mGluR2/3s are primarily responsible for the effects that are being reported in this article and this is consistent with other reports on the effects of group II mGluRs on synaptic activity in the neocortex (Bandrowski et al. 2003). However, mGluR8 activity may be contributing to our findings as well.
Similar issues of specificity can be raised in connection with glutamate transport blockers. tPDC was chosen in the present study because it is reported to be the most potent and specific in blocking glutamate transporter activity. In comparison, another commonly used glutamate uptake inhibitor, DHK, is less potent and has been shown to act directly on postsynaptic glutamate receptors (Bridges et al. 1991; Isaacson and Nicoll 1993; Maki et al. 1994). We also found that DHK caused a depolarization that was not blocked by the NMDA receptor antagonist, AP-5, suggesting an action on postsynaptic AMPA receptors. Our results showed that blocking glutamate transporters, on average, reduced short-term depression at P13–17 but did not convert it to the facilitation that was seen in mature cortex. This indicates that other factors are also important in the developmental regulation of ambient glutamate concentration. This is plausible because developmental changes in the extracellular space could also play a major role in reducing ambient glutamate concentration. Glutamate transporters are localized in both neuron and glial cells (Danbolt 2001). While our results here give no direct information about which type of glutamate transporter accounts for our result, the neuronal glutamate transporter is the most likely candidate because it undergoes a developmental change as indicated in previous immunocytochemical work (Furuta et al. 1997). Some early work on brain slices from adult animals did not detect a consistent and significant effect on synaptic transmission by blocking glutamate transporters (Hestrin et al. 1990; Isaacson and Nicoll 1993). But in culture preparations and younger animals, blocking glutamate transporter activity clearly decreases synaptic responses (Kidd and Isaac 2000; Maki et al. 1994). Our results would suggest that one explanation for this discrepancy would be an age-dependent reduction in activity of glutamate transporters.
Other factors could be contributing to altered ambient glutamate levels in the slices. One possibility is that the older slices were less healthy and, therefore their homeostatic mechanisms for extracellular glutamate were impaired. It is recognized that it is more difficult to get healthy slices from older animals than from younger ones. Although we recorded from deep (30–90 µm beneath the surface of the slice) and healthy cells to eliminate the effect caused by the damage during the slice preparation; we cannot rule out the possibility that tissue trauma caused a decrease in the function of glutamate transporters. In vivo developmental studies would be important to address this issue.
In summary, our results show that tonic activity of mGluRs is an important factor in maturation of synaptic function in the neocortex. This increase in tonic activity is due, in part, to a decreased activity of glutamate transporters. These findings contribute to our understanding of how excitatory synapses go from high release probability with short-term depression to low release probability with short-term facilitation. This appears to be an important step in the functional maturation of excitatory synapses in the neocortex. Ultimately, this may have important implications for our understanding of the dynamic functional differences between mature and immature cortex.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. N. Roper, Dept. of Neurological Surgery, University of Florida, 100 South Newell Dr., Room L2-100, Gainesville, FL 32610 (E-mail: roper{at}neurosurgery.ufl.edu).
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ABSTRACT
INTRODUCTION
, n = 35) and short-term facilitation at the late stage (
, n = 31). Short-term plasticity was measured by normalizing all 5 stimulus-evoked excitatory postsynaptic currents (EPSCs) in a train to the first one.
