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Receptor-Mediated Inhibition of the N-Methyl-O-Aspartate Component of Synaptic Transmission in the Rat Hippocampus

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Receptor-Mediated Inhibition of the N-Methyl-O-Aspartate Component of Synaptic Transmission in the Rat Hippocampus The Journal of Neuroscience, January 1991, 17(l): 203-209 GABA,-Receptor-Mediated Inhibition of the N-Methyl-o-Aspartate Component of Synaptic Transmission in the Rat Hippocampus Richard A. Morrisett,1-5 David D. Mott,2 Darrell V. Lewis,3 H. Scott Swartzwelder,i,4.5 and Wilkie A. Wilson1-*v5 Departments of ‘Medicine (Neurology), *Pharmacology, 3Pediatrics (Neurology) and Neurobiology, and 4Psychology, Duke University Medical Center, Durham, North Carolina 27710. and 5Neurology Research Laboratory, Veterans Administration Medical Center, Durham, North Carolina 27705 GABA receptor regulation of NMDA-receptor-mediated syn- operated channelsare regulated in a voltage-dependentmanner aptic responses was studied in area CA, of the rat hippocam- by Mg2+ (Mayer and Westbrook, 1984; Nowak et al., 1984; pus using extracellular and intracellular recording tech- Herron et al., 1986). Becauseof the development of specific niques. Picrotoxin (PTX) was used to suppress GABA, non-NMDA receptor antagonists such as 6,7-dinitroquinoxa- inhibition and 6,7-dinitroquinoxaline-2,3-dione (DNQX) was line-2,3-dione (DNQX; Drejer and Honor& 1988) the dem- used to suppress non-NMDA receptor-mediated responses. onstration of NMDA-receptor-mediated synaptic potentials has In this manner, we were able to avoid the complicating fac- been facilitated (Blake et al., 1988; Andreasen et al., 1989; Da- tors caused by potentials induced by other excitatory and vies and Collingridge, 1989; Iambert and Jones, 1989). When, inhibitory amino acid receptors. Under these conditions, large in the presenceof DNQX, synaptic inhibition is reduced or NMDA-receptor-mediated EPSPs were observed. When blocked, one can record large depolarizing responsesto NMDA paired stimuli were given at interstimulus intervals from 100 receptor activation (Andreasen et al., 1989; Davies and Collin- to 400 msec, powerful inhibition of the second response was gridge, 1989; Lambert and Jones, 1989; Morrisett et al., 1990b). observed. This inhibition was reversed by the GABA, an- We have recently utilized excitatory amino acid antagonists tagonists phaclofen and P-hydroxy-saclofen; it was also de- in combination with the GABA, antagonist picrotoxin (PTX) pressed by removal of Mg2+ from the bath. Examination of to study NMDA-mediated synaptic potentials (NMDA EPSPs) non-NMDA receptor-mediated synaptic responses (deter- in area CA, of the rat hippocampus in the presenceof Mg2+ mined in the presence of D-2-amino-5-phosphonovalerate (Morrisett et al., 1990a,b). Very large, long-lasting NMDA-re- and PTX) showed no such inhibition, thereby supporting the ceptor-mediated synaptic potentials were recorded in the pres- hypothesis that GABA, inhibition of NMDA EPSPs is post- ence of these drugs. Indeed, the prominent effect of PTX upon synaptic. This difference in paired-pulse inhibition of NMDA the expression of NMDA EPSPs dramatically points up the and non-NMDA EPSPs leads us to conclude that there was apparent role of GABA,-mediated synaptic inhibition in reg- no evidence of GABA,-mediated presynaptic inhibition of ulating the Mg2+ block of NMDA-operated channels.We now excitatory transmitter release. Intracellular recordings in the report that NMDA-mediated synaptic potentials recorded in presence of DNQX and PTX revealed a phaclofen-sensitive dendritic and somatic layers of area CA, of the rat hippocampus late IPSP that correlated in time with the period of inhibition exhibited marked paired-pulse depression.Investigation of this of NMDA responses. Taken together, these data suggest phenomenon revealed that GABA, receptors were responsible that paired-pulse-inhibition of NMDA responses is produced for paired-pulse inhibition of NMDA EPSPs. By this mecha- by a GABA,-receptor-mediated hyperpolarization of the nism, GABA, receptors could participate in the regulation of postsynaptic membrane, causing an enhanced block of the the activity of NMDA-receptor-operated channels and, hence, NMDA channels by Mg2+. Regulation of NMDA-mediated syn- the development of neuronal plasticity. aptic responses by GABA, receptors constitutes a powerful A preliminary report of these findings has been submitted mechanism for control of a major excitatory system in hip- (Morrisett et al., 1990a). pocampal pyramidal cells. Materials and Methods Induction of neuronal plasticity in many systemsis dependent Male Sprague-Dawley rats (1 W-250 gm) were killed under CHCI, an- upon activation of the NMDA subtype of excitatory amino acid esthesia. The hippocampi were rapidly removed, and transverse slices receptor (Harris et al., 1984; Morris et al., 1986; Collingridge 625 wrn thick were prepared. After the slices were allowed to equilibrate for 1 hr in artificial cerebrospinal fluid (ACSF; containing, in mM, NaCl, and Bliss, 1987; Morrisett et al., 1989). However, in many cases, 120; KCl, 3.3; NaH,PO,, 1123; NaHCO,, 25; CaCl,, 1.8; MgSO,, 1.2; the involvement of NMDA receptors in normal synaptic trans- dextrose, 10: continuallv gassed with 95% 0,:5% CO,: oH. 7.4: 32°C). mission is minimal becausethe inward currents via NMDA- a midtemporal slice was transferred to a su&fusion*~hamber’(which contained 1.0 mM MgSO, and 3.0 mM CaCl, in the ACSF unless oth- erwise indicated). Monophasic, constant current stimulus pulses (100 Received May 22, 1990; revised Aug. 10, 1990; accepted Sept. 5, 1990. psec, 100-1000 PA) were generated with a Dagan S-900 stimulator and This work was supported by Grants NS 17701 and AA 07207 and by the were applied through a tungsten stimulus electrode to the Schaffer col- Veterans Administration. R.A.M. is an NRSA fellow (MH 15 I77- 13). laterals in the stratum radiatum of area CA,. Correspondence should lx addressed to Richard Morris&t, Ph.D., Building 16, Extracellular population field potentials were recorded from the stra- Room 25, Veterans Administration Medical Center, Durham, NC 27705. tum radiatum and stratum pyramidale of area CA, using glass micro- Copyright 0 1991 Society for Neuroscience 0270-6474/91/010203-07$03.00/O electrodes filled with 150 mM NaCl (l-3 MQ; Fig. 1). Extracellular 204 Morrisett et al. * GABA,, Inhibition of NMDA-Mediated Synaptic Responses DENDRITIC SOMAE SOMA, ACSF Figure 1. Isolation of NMDA-medi- ated responses in aTea CA,. Population responses recorded from the dendritic DNQX/ and somatic (extracellular) electrodes 1 T I’ (SOMA,) are shown in the first 2 col- PTX umns. The third column shows re- sponses from the intracellular electrode (SOMA,). In the top row, responses re- J corded in the presence of normal ACSF L.f r"- ----IL are presented. In the bottom 2 rows, re- sponses recorded in the presence of the non-NMDA antagonist DNQX ( 10 PM) and the GABA, antagonist PTX (10 DNQX/ FM) are presented. In the bottom row, 1 the effect of the NMDA receptor an- PTX/ tagonist D-APV (50 PM) upon the D-APV r NMDA EPSP induced by DNQX/PTX I 1.2 - ‘O is shown. Stimulus artifacts were omit- mV L I mV L ted for clarity. 20 mrsc 20 mmc recording from the stratum radiatum in ACSF typically elicited re- sponses (see Fig. 1) consisting of a negative-going presynaptic fiber Results volley, immediately followed by a negative-going population field po- tential, reflecting the dendritic excitatory postsynaptic potential. Si- The top row of Figure 1 depicts typical responsesrecorded from multaneous extracellular recording from the stratum pyramidale re- dendritic and somatic sites in area CA,. Although not shown in sulted in a negative-going orthodromic population spike superimposed Figure 1, when the non-NMDA receptor antagonist DNQX (10 upon a positive-going EPSP. Slices were monitored until stable input- PM) was added to the bath, postsynaptic responseswere com- output curves were established. A slice was rejected if the maximal dendritic EPSP recorded from the stratum radiatum was of 1.0 mV pletely abolished. As shown in the middle row of Figure 1, when amplitude or less. the GABA, channel antagonist PTX ( 10 PM) wasadded in com- Intracellular recordings were made from the stratum pyramidale of bination with DNQX to the bath, excitatory post synaptic po- CA, using microelectrodes filled with 4 M K+ acetate (approximately tentials were recorded from the dendritic extracellular electrode. 100 Ma). Intracellular recording typically elicited positive-going EPSPs and action potentials, followed by early and late IPSPs. In every case, Thesedepolarizations (at maximal stimulusintensity) were about CA, pyramidal cells were electrophysiologically identified by stimula- the same amplitude as the control EPSP but of much greater tion of the alveus and intracellular recording of antidromic action po- duration; thus, the area under the NMDA EPSP was approxi- tentials. Neurons were considered acceptable for intracellular recording mately 3 times that of the control EPSP. if all of the following criteria were met: (1) The input resistance was The excitatory responsesrecorded in the combination of greater than 30 Ma, (2) the action-potential spike height was greater than 50 mV, and (3) the resting membrane potential was less than -60 DNQX and PTX were presumed to be initiated by activation mV. A total of 11 neurons was utilized for this study. of NMDA receptors. NMDA EPSPswere accompanied by re- To elicit the NMDA component of synaptic transmission (NMDA petitive cell firing in both individual cells and in the population EPSP) in the presence of Mg*+, 10 PM DNQX and 10 PM picrotoxin response.Addition of the NMDA receptor antagonist D-APV were added to the ACSF. The response typically became stable within 30-45 min, and input-output curves were obtained for the NMDA to the bath containing DNQX and PTX almost completely abol- EPSPs and intracellular responses. ished the EPSP recorded extracellularly and blocked cell firing. Extracellular dendritic waveforms were analyzed on a Compaq 386s In separateexperiments, theseresponses have been demonstrat- computer using Waveform Basic software (Blue Feather Software for ed to be almost completely blocked by the NMDA channel Nicolet Corp., Madison, WI). A program, written in this laboratory in antagonist MK-80 1 (10 MM; data not shown).
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