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Training in the Morris Water Maze Occludes the Synergism Between Downloaded from learnmem.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Training in the Morris Water Maze Occludes the Synergism Between ACPD and Arachidonic Acid on Glutamate Release in Synaptosomes Prepared from Rat Hippocampus Bernadette McGahon, 1 Christian Holscher, 2 Liam McGlinchey, 2 Michael J. Rowan, 2 and Marina A. Lynch 1,3 1Department of Physiologyand 2Department of Pharmacologyand Therapeutics Trinity College Dublin 2, Ireland Abstract In~oducUon It is a widely held view that memory forma- We here that release of glutamate, report tion is dependent on changes in synaptic efficacy inositol phospholipid metabolism, and that allows strengthening (or weakening) of asso- protein kinase C (PKC) activity are ciations between neurons. The hippocampus has increased in synaptosomes prepared from been identified as a brain area that plays a signifi- hippocampi of rats that had been trained in cant role in memory processing (Squire 1992), a spatial learning task. In hippocampi particularly processing of spatial memory (e.g., obtained from animals that were untrained, McNaughton et al. 1986; O'Keefe 1991), and activation of the metabotropic glutamate though it has been extensively studied, the mech- receptor by the specific agonist anisms that underlie acquisition and recall are not trans, l.amino.cyclopentyl, l ,3.dicarboxylate known. Certain cellular changes have been associ- (ACPD) increased release of glutamate but ated with learning; many of these have been iden- only in the presence of a low concentration tiffed as a result of comparison between young of arachidonic acid. A similar interaction animals, which perform well in learning tasks, and between arachidonic acid and ACPD was aged animals, which often exhibit learning impair- observed on inositol phospholipid turnover ments (Barnes 1979), and in studies designed to and on PKC activity. However, the investigate similarities and/or differences between synergistic effect of arachidonic acid and learning and long-term potentiation (LTP). The ACPD on glutamate release was occluded in hypothesis that LTP in the hippocampus is a bio- hippocampal synaptosomes prepared from logical correlate of learning and/or memory is ac- trained rats. Occlusion of the effect on tively challenged, but there is a good deal of indi- inositol phospholipid turnover and PKC rect evidence lending support to this idea. Thus, it activation was also observed. These data has been reported that AP5 blocks induction of suggest that the molecular changes that LTP (see Bliss and Collingridge 1993) and also the underlie spatial learning may include ability of rats to perform in a spatial learning task activation of metabotropic glutamate (Morris et al. 1986), that both LTP and learning receptors in the presence of arachidonic are associated with increased release of glutamate acid and that the interaction between in dentate gyrus (Richter-Levin et al. 1994), and arachidonic acid and ACPD triggers the that protein kinase C (PKC) activity is increased presynaptic changes that accompany following induction of LTP (Akers et al. 1986; An- learning. genstein et al. 1994) and in a learning paradigm (Fordyce et al. 1994). 3Corresponding author. It has been reported recently that when acti- LEARNING & MEMORY 3:296-304 9 1996 by Cold Spring Harbor Laboratory Press ISSN1072-0502/96 $5.00 L E A R N I N G & M E M O R Y 296 Downloaded from learnmem.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press TRAINING OCCLUDES SYNERGISM BETWEEN ACPD AND AA vation of metabotropic glutamate receptors is used in these experiments. The platform (diam., blocked, learning in a spatial task is impaired 10 cm) was 4 cm below the water surface during (Richter-Levin et al. 1994), and this observation, training. The water was kept at 23-+2~ and made as well as the finding that learning was accompa- opaque with titanium dioxide. The pool was situ- nied by increased glutamate release in dentate gy- ated in a room with visual cues (e.g., door, win- rus, brings into the context of learning and recall dow, curtain, etc.). All animals were marked with the reports that trans-1-amino-cyclopentyl-1, 3-di- a black water-resistant marker to allow monitor- carboxylate (ACPD) and arachidonic acid (AA) act ing. The animals' movements were recorded with synergistically to increase release of glutamate in a video camera attached to the ceiling, and data cortex (Herrero et al. 1992) and hippocampus was analyzed using a tracking program written by (McGahon and Lynch 1994). AA has not yet been James Mahon (Trinity College, Dublin). During shown to play a role in spatial learning, but it has task aquisition, the program measured latency of been implicated in learning in the chick (HGlscher animals to reach the platform and the distance and Rose 1994), and rat (H/~lscher et al. 1995) covered. The pool was divided into four arbitrary and in maintenance of LTP in the dentate gyrus of quadrants for transfer test analysis. The quadrant the rat (Williams et al. 1989; Clcments et al. 1991; in which the platform had been located (SE) was Lynch and Voss 1994). designated the target quadrant. During the transfer In designing these experiments, we consid- test, the percentage of the distance covered was ered that changes at the level of the synapse, re- assessed for each of the four quadrants. suiting in "strengthening" of these synapses, prob- Animals were placed in the water at one of ably accompany spatial learning and that presyn- four starting positions that alternated in a clock- aptic modifications are likely to contribute to wise manner. Six trials were performed per day, these changes. In this study we have examined the and the intertrial interval was -5 min. The cut-off effect of spatial learning on three parameters in time for a trial, if the animals failed to locate the hippocampal synaptosomes: glutamate release, platform, was 120 sec; in this case the animals inositol phospholipid metabolism, and PKC activa- were manually placed on the platform for 10 sec. tion. In addition we have compared the effect of On day 4, the platform was removed and the ani- AA and ACPD, alone and in combination, on these mals were given a 60-see duration transfer test in three parameters in synaptosomes prepared from the pool. The group that did not learn the task hippocampus obtained from untrained rats and were given six swimming sessions in the pool each hippocampus obtained from rats that had been day without a platform. The duration of the session trained to locate a hidden platform in the Morris was the same as that of the group of animals that water maze. The data presented indicate that spa- learned the task. tial learning increases glutamate release, inositol Animals were sacrificed by cervical disloca- phospholipid metabolism, and PKC activation. tion 1 O-15 min after completion of the behavioral Moreover, although AA and ACPD interact to fur- test. The hippocampus was dissected free; the time ther increase all three measures in synaptosomes taken for this dissection was -1 min. Slices (350 prepared from untrained tissue, this effect is oc- p~m) were prepared using a Mcllwain tissue chop- cluded in hippocampus obtained from trained rats. per, suspended in Krebs solution, thoroughly mixed, and divided into three aliquots for later Materials and Methods assessment of glutamate release, inositol phospho- lipid metabolism, and PKC activity. Slices were fro- ANIMALS zen in Krebs solution containing 10% DMSO (Haan and Bowen 1981 ) and stored in three sep- Male Wistar rats (250-300 grams) were used arate aliquots in liquid N 2 until required for anal- in these experiments. Animals were housed in ysis. groups of four to six under a 12-hr light schedule. The temperature was controlled between 22~ and 23~ TISSUE PREPARATION Slices were thawed rapidly ( 1.5-2 min) by ag- TRAINING SCHEDULE itation at 37~ and rinsed four times in excess A white fiberglass circular pool (diam., 120 fresh oxygenated Krebs solution. Tissue was ho- cm; height, 48 cm; depth of water, 34 cm) was mogenized in 0.32 M ice-cold sucrose and centri- L E A R N I N G & M E M O R Y 297 Downloaded from learnmem.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press McGahon et al. fuged at 5000 rpm for 5 min. The crude synapto- founding effects. In preliminary experiments, re- somal pellet, P2, was prepared by centrifuging the lease of [3H]glutamate was compared in synapto- resulting supernatant at 15,000 rpm for 15 min. P2 somes prepared in sucrose alone and in sucrose to was used for analysis of glutamate release, inositol which bovine serum albumin (BSA) was added to phospholipid metabolism, and PKC activity. All remove polyunsaturated fatty acid that may have biochemical analysis was completed on all samples been released during preparation. No difference that were tested in the behavioral paradigm. between the two groups was observed, and, so, the experiments described here were performed on slices that were prepared in the absence of BSA. ASSESSMENT OF GLUTAMATE RELEASE Synaptosomes were resuspended in ice-cold ANALYSIS OF INOSITOL PHOSPHOLIPID TURNOVER Krebs solution (composition in mM: NaCI, 136; KCI, 2.54; KH2PO4, 1.18; MgSO4.7H20 , 1.18; To examine [3H]inositol labeling of phosphoi- NaHCO3, 16; glucose, 10) containing 2 mM CaCl 2 nositides and inositol phosphates, synaptosomes and incubated for 15 min at 37~ in the presence were resuspended in oxygenated ice-cold Krebs of [3H]glutamate (Amersham, UK; specific activity, buffer (composition in mM: NaCI, 136; KCI, 2.54; 20-40 Ci/mmole; final concentration, 5 • 10 -7 KJJ2PO4, 1.18; MgSO4.7H20 , 1.18; NaHCO3, 16; mi). Tissue was aliquoted onto Millipore filters CaCI 2, 1.3; glucose, 10; cytidine, 1; LiCI, 5) and (0.45 ixm) and rinsed under vacuum at least 20 aliquots (50 Ixl) were incubated at 37~ for 35 times by addition of 250 p~l of ice-cold, oxygen- min in a shaking water bath in 120 pA Krebs buffer ated, fresh Krebs solution to the filter papers.
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