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Modulation of N-Methyl-D-Aspartate Receptor Function by Glycine Transport

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Modulation of N-Methyl-D-Aspartate Receptor Function by Glycine Transport Proc. Natl. Acad. Sci. USA Vol. 95, pp. 15730–15734, December 1998 Neurobiology Modulation of N-methyl-D-aspartate receptor function by glycine transport RICHARD BERGERON,TORSTEN M. MEYER,JOSEPH T. COYLE*, AND ROBERT W. GREENE Laboratory of Neuroscience, Department of Psychiatry, Harvard Medical School, 115 Mill Street, Belmont, MA 02178-9106 Communicated by Seymour S. Kety, National Institute of Mental Health, Westwood, MA, October 21, 1998 (received for review August 25, 1998) ABSTRACT The recent discovery of glycine transporters glycine and GLYT1 on synaptic currents elicited by stimulation in both the central nervous system and the periphery suggests of the CA3-CA1 Schaffer collateral axons in hippocampal that glycine transport may be critical to N-methyl-D-aspartate slices of the rat in vitro. receptor (NMDAR) function by controlling glycine concen- tration at the NMDAR modulatory glycine site. Data obtained from whole-cell patch–clamp recordings of hippocampal py- METHODS ramidal neurons, in vitro, demonstrated that exogenous gly- Whole-cell recordings were obtained with a technique modi- cine and glycine transporter type 1 (GLYT1) antagonist fied from Blanton et al. (18). Briefly, borosilicate glass elec- selectively enhanced the amplitude of the NMDA component trodes (resistance, 4–6 MV) were filled with 120 mM potas- y y y y of a glutamatergic excitatory postsynaptic current. The effect sium gluconate 10 mM KCl 3 mM MgCl2 10 mM Hepes 2 y y was blocked by 2-amino-5-phosphonovaleric acid and mM K2ATP 0.2 mM Na2GTP 0.25% biocytin. The pH was 7-chloro-kynurenic acid but not by strychnine. Thus, the adjusted at 7.2 with KOH. During the experiments, the slices glycine-binding site was not saturated under the control were perfused continuously with artificial cerebral fluid con- conditions. Furthermore, GLYT1 antagonist enhanced y y y sisting of 124 mM NaCl 2mMKCl 1.3 mM MgCl2 2.5 mM NMDAR function during perfusion with medium containing y y y m CaCl2 3mMKH2PO4 10 mM glucose 26 mM NaHCO3. The 10 M glycine, a concentration similar to that in the cere- osmolarity of the artificial cerebral fluid was 315 mosmol, the in vivo brospinal fluid , thereby supporting the hypothesis that pH was adjusted at 7.35, and the temperature was maintained the GLYT1 maintains subsaturating concentration of glycine at 35°C. For the series of experiments with 6,7-dinitroquinoxa- at synaptically activated NMDAR. The enhancement of 1 line-2,3-dione (DNQX) and bicuculline, a low-Mg2 solution NMDAR function by specific GLYT1 antagonism may be a was used (0.1 mM MgCl y3.7 mM CaCl ) to maintain same the feasible target for therapeutic agents directed toward diseases 2 2 related to hypofunction of NMDAR. extracellular cation concentration. Drugs were applied to the perfusion medium by using multiple perfusion lines that funneled into a single outlet near the recording area. Thus, any N-methyl-D-aspartate receptors (NMDAR) play a crucial role one of the multiple lines could be selected, allowing for fast in several aspects of fast excitatory neurotransmission includ- (1–10 sec) switching between different media. ing the gating of an excitatory conductance with partial Postsynaptic currents (PSCs) were evoked with bipolar permeability to calcium (1) and, in some regions, long-term stimulation of the Schaffer collaterals. The stimulation inten- synaptic plasticity (2). Modulation of the NMDAR function sity was adjusted to evoke PSC amplitude in the range of occurs at a number of sites that are distinct from the glutamate- 52 6 binding site (3). One of these sites is the strychnine-insensitive 75–100 pA at Vh 60 mV. Data are expressed as the mean binding site where glycine acts to allosterically facilitate SE. For the experimental series with bicuculline and DNQX, NMDAR function (4–6). the magnesium concentration was used to increase the ampli- Glycine is a necessary coagonist (7), potentiating NMDAR tude of the NMDA-dependent current to a degree that could function in a wide variety of preparations of cerebral cortex be observed easily (19). This was necessary, at least in part, with an apparent dissociation constant in the range from about because of the competitive antagonism of the glycine site by 100 to 300 nM (8). Glycine-dependent enhancement of ion- DNQX (20–22). For this series of experiments, we have tophoretically applied NMDA and of the NMDA component measured the amplitude of the excitatory PSC (EPSC) at Vh of an evoked synaptic potential in cortical slices in vitro has 5255 mV. been demonstrated (6); however, the effective concentration The glycine derivative, N[3-(49-fluorophenyl)-3-(49- of the applied glycine could not be determined and its phys- phenylphenoxy)propyl]sarcosine (NFPS; Fig. 1), is a selective iological role in NMDAR modulation remains unclear (9). and potent inhibitor of GLYT1 in the rat brain with a Ki of 5 This is in large part because the concentration of glycine in the nM and no effect on the activity of GLYT2. Similarly, NFPS cerebrospinal fluid is about 6 mM (10), which ought to saturate had no measurable effect on the amino acid transport of either the NMDAR glycine site. proline, glutamate, or g-aminobutyric acid (GABA). At a The recent molecular and biochemical characterization of a concentration of 100 mM, this compound does not displace the class of glycine transporter proteins (11–14) in brain suggests binding of [H]3MDL-105,519 to the NMDA glycine site, that the glycine concentration in microdomains may be regu- [H]3AMPA, or [H]3kainate binding. Under conditions of high lated by these transporters. Of these, the glycine transporter NMDA channel activity (10 mM glutamatey200 mM glycine), type 1 (GLYT1) is expressed primarily in glia and neurons of the neocortex and archicortex in association with regions of Abbreviations: NMDAR, N-methyl-D-aspartate receptor; PSC, high NMDA expression (15–17). We examined the role of postsynaptic current; EPSC, excitatory PSC; IPSC, inhibitory PSC; GABA, g-aminobutyric acid; DNQX, 6,7-dinitroquinoxaline-2,3- a The publication costs of this article were defrayed in part by page charge dione; AMPA, -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid; NFPS, N[3-(49-fluorophenyl)-3-(49-phenylphenoxy)propyl]sar- payment. This article must therefore be hereby marked ‘‘advertisement’’ in cosine; APV, 2-amino-5-phosphonopentanoic acid; GLYT1 and accordance with 18 U.S.C. §1734 solely to indicate this fact. GLYT2, glycine transporter type 1 and 2, respectively. © 1998 by The National Academy of Sciences 0027-8424y98y9515730-6$2.00y0 *To whom reprint requests should be addressed. e-mail: jcoyle@ PNAS is available online at www.pnas.org. warren.med.harvard.edu. 15730 Downloaded by guest on September 27, 2021 Neurobiology: Bergeron et al. Proc. Natl. Acad. Sci. USA 95 (1998) 15731 rats in vitro enhanced the amplitude of the Schaffer collateral- evoked PSC by 44.5 6 7.5% (n 5 13; P , 0.005, Wilcoxon signed-ranks test; Fig. 2A). This enhancement was blocked completely by the NMDAR antagonist 2-amino-5-phospho- nopentanoic acid (APV; 50 mM; n 5 5; data not shown). The PSC elicited by Schaffer collateral stimulation is a compound EPSC–inhibitory PSC (IPSC). NMDAR can gate cationic channels that contribute to the EPSC (24, 25) and to the excitatory drive on interneurons responsible for the IPSC (26). The following analysis is concerned with the effects on 52 the EPSC component measured at Vh 60 mV that are most easily observed as a change in the PSC amplitude. The IPSC component contributes primarily the rate of the PSC decay. The effect of a selective GLYT1 antagonist, NFPS, was assessed. GLYT1 antagonist (100 nM) enhanced the ampli- tude of the evoked PSC by 50.4 6 9.8% (n 5 18; P , 0.005; Wilcoxon signed-ranks test; Fig. 2B). The enhancement was dependent on NMDAR-mediated neurotransmission as it was FIG. 1. The chemical structure for N[3-(49-fluorophenyl)-3-(49- blocked by APV (50 mM; n 5 8; Fig. 3A). In the presence of phenylphenoxy)propyl]sarcosine. an antagonist of the NMDAR glycine site (27), 7-chlo- m [H]3MK-801 binding also is not affected (J. F. McKelvey, L. A. rokynurenic acid (5 M), GLYT1 antagonist had no effect Borden, and H. C. Fibiger, personal communication). (n 5 10; Fig. 3B). Since glycine can gate a chloride conductance via activation RESULTS of a strychnine-sensitive receptor, we examined the effect of strychnine (25 mM). By itself, strychnine enhanced the am- In agreement with a previous report (23), exogenous glycine (10 mM) applied to hippocampal slices from 8- to 12-week-old FIG. 3. When APV (A,50mM) and 7-Cl-Kyn (B,5mM) were added to the medium, the enhancing effect of GLYT1 antagonist was blocked completely, suggesting a selective effect on the NMDA component of the PSC. (C) However, the addition of strychnine (25 mM), an antagonist of the glycine-gated chloride channel, did not block the enhancing effect of FIG. 2. Glycine and GLYT1 antagonist enhanced the PSC evoked GLYT1 antagonist (100 nM). Each trace is the average of five PSCs (Vh by Schaffer collateral stimulation. (A) Glycine (10 mM) increased the 5260 mV). (D) The histogram shows the percentage of change of the amplitude of the evoked PSCs. (B) GLYT1 antagonist (100 nM) also amplitude of the PSC induced by APV (50 mM) and APV (50 mM) plus increased the amplitude of the evoked PSCs. Each trace is the average GLYT1 antagonist (100 nM), and 7-Cl-Kyn (5 mM) and 7-Cl-Kyn (5 mM) of 5 PSCs (Vh 5260 mV). (C) The histogram shows the percentage plus GLYT1 antagonist (100 nM).
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