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The Glutamate Uptake Inhibitor L- Trans=Pyrrolidine=2,4=Dicarboxylate Depresses Excitatory Synaptic Transmission Via a Presynapt

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The Glutamate Uptake Inhibitor L- Trans=Pyrrolidine=2,4=Dicarboxylate Depresses Excitatory Synaptic Transmission Via a Presynapt The Journal of Neuroscience, November 1994, 14(11): 6754-6762 The Glutamate Uptake Inhibitor L- Trans=pyrrolidine=2,4=dicarboxylate Depresses Excitatory Synaptic Transmission via a Presynaptic Mechanism in Cultured Hippocampal Neurons Reiko Maki,’ Michael B. Robinson,lJ and Marc A. Dichter1-2 ‘David Mahoney Institute of Neurological Sciences and *Departments of Neurology and Pharmacology, University of Pennsylvania, School of Medicine and The Graduate Hospital, and 3The Children’s Seashore House, Children’s Hospital of Philadelphia, and Departments of Pediatrics and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104 Sodium-dependent high-affinity uptake of glutamate is Most previous studies on the involvement of reuptake in ex- thought to play a major role in the maintenance of very low citatory synaptic transmissionhave shown potentiated neuronal extracellular concentrations of excitatory amino acids (EAA), responsesto exogenous/yapplied glutamate (Lodge et al., 1979, and may modulate the actions of released transmitter at 1980; Johnston et al., 1980; Saweda et al., 1985; Brodin et al., G-protein-coupled receptors and extrasynaptic receptors 1988; Hestrin et al., 1990). However, the temporal and spatial that are activated over a longer distance and time course. characteristics of exogenousapplication of glutamate may be We have examined the effects of the recently developed very different from synaptically released transmitter. Ionto- uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-Wan+ phoretically applied transmitters are not localized to the syn- PDC) on monosynaptically evoked excitatory postsynaptic apse, exist in nonphysiologic concentrations, and affect both currents (EPSCs) in very-low-density cultures of hippocam- synaptic and extrasynaptic receptors, and are therefore more pal neurons. L-Trans-PDC produced a decreased amplitude susceptible to slow removal processesby neuronal and glial of both the non-NMDA and NMDA receptor-mediated com- transporters. ponents of monosynaptically evoked EPSCs. Examination of Recent studieshave addressedthe effects of uptake inhibition miniature EPSCs (mEPSCs) indicated that changes in the on the time course of excitatory postsynaptic currents (EPSCs). sensitivity of postsynaptic non-NMDA receptors did not un- Dihydrokainate (DHK), a glutamate uptake inhibitor, did not derlie the decrease in evoked EPSC amplitudes. The me- affect the non-NMDA component of evoked EPSCs in CA1 tabotropic receptor agonist (1 S,3R)-1 -aminocyclopentane- neurons of hippocampal slicesbut did increasethe amplitude, 1,3-dicarboxylic acid (1 S,3R-ACPD) also depressed both but not the duration, of the NMDA receptor-mediated com- components of the EPSC. The competitive metabotropic re- ponent (Hestrin et al., 1990). However, DHK is a weak inhibitor ceptor antagonist (RS)-a-methyl-4-carboxyphenylglycine of glutamate uptake, and directly activates postsynaptic EAA (MCPG) blocked the depression of EPSC amplitude induced receptors (Bridges et al., 1991; seealso Results). Sarantis et al. by 1 S,3R-ACPD and also blocked the effects of L-&ens-PDC. (1993) investigated the effects of the potent and selective uptake Finally, low concentrations of L-glutamate (2 FM) mimicked inhibitor L-truns-pyrrolidine-2,4-dicarboxylate (L-truns-PDC) the effects of L-trans-PDC on EPSC amplitude. From these on synaptic currents in hippocampal and cerebellar slices. results we conclude that the application of L-trans-PDC to L-Truns-PDC at 300 PM decreasedthe NMDA component of cultured hippocampal neurons results in the activation of EPSCs,whereas the non-NMDA EPSCswere either unaffected presynaptic metabotropic receptors, leading to a decrease or slightly reduced in amplitude, with no effect on the decay in synaptic transmission. We propose that this effect is due time constant. Isaacsonand Nicoll (1993) reported that while to an increase in ambient glutamate concentrations following L-truns-PDC potentiated the effects of exogenouslyapplied glu- inhibition of glutamate uptake, resulting in presynaptic in- tamate in hippocampal slices,synaptically evoked EPSCswere hibition of excitatory synaptic transmission. unaffected. The time course of the EPSCs was unchanged; a [Key words: EPSC, mEPSC, L-Trans-PDC, EAA uptake in- small and variable decreasein the peak amplitude of the EPSC hibition, ACPD, MCPG, tissue culture, patch clamp] in a fraction of the cells was noted. Application of L-truns-PDC to these hippocampal slicesresulted in an elevation of the ex- tracellular levels of glutamate. Very recently, Mennerick and Zorumski (1994) reported that inhibition of glutamate uptake by glial depolarization, Li+, or hydroxyaspartate prolonged the Received Jan. 7, 1994; revised Apr. 22, 1994; accepted May 5, 1994. decay rate of non-NMDA autaptic currents in the presenceof We thank Drs. Karen Wilcox and Louis Littman for critical review of the cyclothiazide (in order to block non-NMDA receptor desensi- manuscriot and advice. Ms. Kav Cherian and Ms. Maraaret’Price for oreoaration and maintenance of thk tissue &ores, and Mr. J. Josh Lawrence f& t;chnical tization), as well as the decay rate of NMDA autaptic currents assistance. This work was supported by GM-3478 1 (M.A.D., M.B.R.), AG- 12003- in cultured hippocampal single-neuron microislands. To date, 0 I (R.M.), NS29868 (M.B.R.), and NS24260 (M.A.D.). this is the only demonstration that inhibition of glutamate up- Correspondence should be addressed to Marc A. Dichter, M.D., Ph.D., De- partment of Neurology, Graduate Hospital, 19th and Lombard Streets, Philadel- take may affect the time course of the postsynaptic response. phia, PA 19146. Inhibition of glutamate uptake, and the subsequentaccu- Copyright 0 1994 Society for Neuroscience 0270-6474/94/146754-09$05.00/O mulation of extracellular glutamate, could have both presyn- The Journal of Neuroscience, November 1994, 14(11) 6755 aptic and postsynaptic consequences. Rapid desensitization of the neurons with various extracellular solutions was achieved using a the quisqualate/AMPA receptors (Tang et al., 1989; Trussel and peristaltic pump. The antagonist MCPG was coapplied with either lS,3R- ACPD or L-truns-PDC by bath perfusion. Fischbach, 1990) by ambient concentrations of glutamate could The internal solution of the whole-cell patch electrode for mEPSC result in a decreased amplitude of the EPSC. An increase in the recordings contained (in mM) CsCl. 140: EGTA. 2: HEPES. 10: ducose. NMDA component of the EPSC may also be expected, given 10; ATPlMg2+, 4 (pH 7.4, 290-30b m&m). For the paired rec&dingsl the high affinity of the NMDA receptor for glutamate (Patneau 140 mM K-gluconate was used as the major ionic constituent to allow and Mayer, 1990). Conversely, accumulated glutamate could excitatory postsynaptic currents (EPSCs) to be readily distinguished from inhibitory postsynaptic currents (IPSCs) on the basis of reversal feed back onto presynaptic autoreceptors and depress EPSC potential; the reversal potential for IPSCs with potassium gluconate amplitude (Forsythe and Clements, 1990; Baskys and Malenka, electrodes is approximately -50 mV, whereas the reversal potential for 199 1; Pacelli and Kelso, 199 1; Desai and Conn, 1992). In fact, EPSCs remains between 0 and + 10 mV. inhibition of GABA uptake produces a decrease in the ampli- Pharmacologic compounds used in these experiments included bi- tude of GABA-mediated IPSCs between hippocampal neurons cuculline methiodide (10 PM), APV (100 PM) (both from Sigma), CNQX (10 WM) (Research Biochemicals Inc.), TTX (3 PM) (Calbiochem), di- in culture by acting in an analogous manner; activation of pre- hydrokainate (1 mM) (Cambridge Research Biochemical& D,r,-fl-threo- synaptic GABA, receptors decreases neurotransmitter release hydroxyaspartate (50 PM) (Calbiochem), L- aspartate-P-hydroxamate (Oh and Dichter, 1994). (100 UM) (Sinma). L-trans-PDC (100. 250 UM). (lS.3R)-l-aminocvclo- In the experiments reported here, we have examined the ef- pen&e: 113~dicarboxylic acid (1 S, 3R-ACPD5 ‘106 &I), and (Rk)-cy- methyl-4-carboxyphenylglycine (MCPG; 500 PM) (all from To& Neu- fects of L-truns-PDC on excitatory synaptic transmission be- ramin). tween hippocampal neurons in very-low-density culture. L- Trans- GH-glutamate transportassays. Inhibition of uptake of LJH-glu- PDC potently inhibits glutamate uptake in these cultures, and tamate was measured as previously described (Robinson et al., 1991) does not induce a sizeable inward current, unlike previously with some minor modifications. Triplicate assays were performed in a L-Truns-PDC significantly decreased the final volume of 0.5 ml of HBS containing 2 mM CaCl, and 0 Mg*+ in used uptake inhibitors. the presence and absence of L-trans-PDC.In parallel assays, uptake was amplitudes of both the non-NMDA and NMDA receptor-me- measured in the absence of sodium by substituting equimolar choline diated componentsof monosynaptically evoked EPSCsbetween chloride for the NaCl in the HBS. All assav comnonents were added to pairs of hippocampal cells. This appeared to be due to a pre- cultures grown in 12-well 22 mm culture plates (Coming). Assays were synaptic mechanism,possibly due to an increasedconcentration performed at room temperature and stopped after a 5 min incubation by addition of 2 ml of cold (4°C) choline-containing buffer. The cells of ambient glutamate feeding back onto presynaptic metabo- were rinsed three times with 1 ml of ice-cold choline-containing buffer, tropic glutamate receptors to decrease neurotransmitter release. and
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