Biomedical subjects

B McGahon

Publications and source records attributed to B McGahon.

9 recordsLinked to original sources

PubMed1999

Activation of p42 mitogen-activated protein kinase by arachidonic acid and trans-1-amino-cyclopentyl-1,3- dicarboxylate impacts on long-term potentiation in the dentate gyrus in the rat: analysis of age-related changes.

Maintenance of long-term potentiation in perforant path-granule cell synapses is associated with an increase in glutamate release, which we have suggested relies on an interaction between arachidonic acid and the metabotropic glutamate receptor agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD). Evidence suggests that this interaction is dependent on stimulation of tyrosine kinase, which phosphorylates and activates phospholipase Cgamma. In this study, we demonstrate that arachidonic acid and ACPD stimulate tyrosine phosphorylation of a protein of about 40,000 mol. wt and further analysis, using a specific antibody, suggested that this may be extracellular signal-regulated kinase, one member of the family of mitogen-activated protein kinases. Activity of extracellular signal-regulated kinase was increased by arachidonic acid and ACPD in vitro, but it was also increased by induction of long-term potentiation in perforant path-granule cell synapses. A role for extracellular signal-regulated kinase in long-term potentiation was supported by the observation that expression of long-term potentiation, as well as the associated increases in endogenous glutamate release and extracellular signal-regulated kinase activation, were inhibited by pretreatment with the mitogen-activated protein kinase inhibitor, PD98059, while PD98059 pretreatment inhibited the interaction between arachidonic acid and ACPD on glutamate release. An age-related decrease in extracellular signal-regulated kinase activity was observed in the dentate gyrus, and there was no evidence of increased extracellular signal-regulated kinase activity or endogenous glutamate release in tissue prepared from aged rats in which long-term potentiation was compromised. The evidence is consistent with the view that increased activation of extracellular signal-regulated kinase plays a role in long-term potentiation, and that activation of this kinase relies on the interaction between arachidonic acid and ACPD.

Aging↗

PubMed1998

Analysis of the interaction between arachidonic acid and metabotropic glutamate receptor activation reveals that phospholipase C acts as a coincidence detector in the expression of long-term potentiation in the rat dentate gyrus.

We have reported that arachidonic acid and the metabotropic glutamate receptor agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD), act in synergy to increase release of glutamate from synaptosomes prepared from rat dentate gyrus. The observation that prior induction of LTP in perforant path-granule cell synapses occluded this synergism suggested that the interaction between arachidonic acid and ACPD might trigger the increase in glutamate release that accompanies LTP in dentate gyrus. Our objective was to identify the mechanism underlying the synergism between arachidonic acid and ACPD in LTP. The data indicate that both agents activate phospholipase C(PLC); the arachidonic acid-induced increase in phospholipase C activation was inhibited by the tyrosine kinase inhibitor, genistein, suggesting that PLCgamma, which is stimulated by tyrosine phosphorylation may be activated by arachidonic acid. The ACPD-induced increase was inhibited by neomycin, indicating the involvement of a G-protein and suggesting that PLCbeta may be activated by ACPD. We report that arachidonic acid stimulated phosphorylation of the specific tyrosine kinase substrate, poly(Glu80,Tyr20) and direct analysis indicated that arachidonic acid increased phosphorylation of PLCgamma. PLCgamma phosphorylation was assessed in control dentate gyrus and dentate gyrus in which LTP was induced in vivo. We report that the tyrosine kinase inhibitor, genistein, blocked expression of LTP and also blocked the associated increase in phosphorylation of PLCgamma. The data presented here indicate that tyrosine phosphorylation of PLCgamma was significantly enhanced following induction of LTP, but in separate experiments, in which LTP was inhibited by intraventricular injection of genistein, phosphorylation of PLCgamma was inhibited. The evidence presented is consistent with the hypothesis that PLC acts as a coincidence detector in LTP. The data indicate that PLCbeta is activated by ACPD, PLCgamma is activated by arachidonic acid, and coincident activation of both isoforms is necessary to stimulate an increase in glutamate release.

Animals↗

PubMed1998

Analysis of the effect of membrane arachidonic acid concentration on modulation of glutamate release by interleukin-1: an age-related study.

Aging is associated with a change in membrane composition that includes a decrease in membrane polyunsaturated fatty acids, including arachidonic acid, and an increase in membrane cholesterol. Alterations in membrane structure are likely to impact on transmitter release, which relies on the fusion of synaptic plasma and synaptic vesicle membranes, and it may therefore be the underlying cause of the age-related decrease in glutamate release in hippocampal preparations. Recent evidence indicates that interleukin-1, by binding with its receptor, inhibits glutamate release in hippocampal synaptosomes prepared from young but not aged rats. The age-related attenuated effect may be due to impaired ligand-receptor interactions arising from the change in membrane composition, which should theoretically be reversed by increasing membrane polyunsaturated fatty acid concentration. To test this hypothesis, we have investigated the effect of a diet supplemented with arachidonic acid and its precursor, gamma-linolenic acid, on membrane arachidonic acid concentration, glutamate release and on the release response to interleukin-1 in hippocampal tissue prepared from aged and young rats. We report that dietary supplementation reversed the age-related changes in membrane arachidonic acid and expression of IL-1beta. We also present data that indicate that the age-related decrease in glutamate release from hippocampal synaptosomes was reversed in aged animals that had been fed on the experimental diet. The data support the view that changes in membrane composition contribute to certain age-related deficits, in particular the decrease in glutamate release observed in hippocampal synaptosomes.

Aging↗

PubMed1997

The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed.

The ability of aged rats to sustain long-term potentiation in the dentate gyrus of the hippocampus is impaired and this impairment correlates with decreased release of glutamate and a decrease in membrane arachidonic acid concentration. Twenty-two-month-old rats receiving a diet supplemented with arachidonic acid and its precursor, gamma-linolenic acid, sustained long-term potentiation in a manner indistinguishable from four-month-old controls. Dietary supplementation also restored arachidonic acid concentrations in membranes prepared from hippocampus of these aged animals to levels observed in hippocampus of four-month-old rats. Glutamate release stimulated by depolarization was similar in dentate gyrus prepared from young rats and aged rats which received the experimental diet, but was markedly reduced in aged animals which received the control diet. In addition, the synergism between arachidonic acid and the metabotropic glutamate receptor agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate, on glutamate release, which was observed in hippocampal synaptosomes prepared from four-month-old rats, was also observed in hippocampal preparations obtained from aged rats which had been fed with the experimental diet, but was absent in hippocampal preparations obtained from aged animals which were fed with control diet. Thus, reversing the age-related decrease in membrane arachidonic acid concentration restored ability of aged animals to sustain long-term potentiation and reversed age-related changes in glutamate release.

Aging↗

PubMed1996

The synergism between ACPD and arachidonic acid on glutamate release in hippocampus is age-dependent.

Activation of the metabotropic glutamate receptor by the specific agonist trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD) increases release of glutamate and activation of protein kinase C in the presence of a low concentration of arachidonic acid in hippocampal synaptosomes prepared from 4-month-old rats. The data presented indicate an age-related decrease in both [3H]glutamate release and protein kinase C activation and an age-related decrease in the release response to arachidonic acid and ACPD, with no corresponding change in protein kinase C activation. The finding that the interaction between arachidonic acid and ACPD on release was absent in synaptosomes prepared in the presence of heparin, an antagonist at inositol trisphosphate receptors, suggests that mobilization of intracellular calcium stores plays a role in the synergism between arachidonic acid and ACPD on [3H]glutamate release in hippocampal synaptosomes.

Aging↗

PubMed1996

The synergism between metabotropic glutamate receptor activation and arachidonic acid on glutamate release is occluded by induction of long-term potentiation in the dentate gyrus.

In synaptosomes prepared from dentate gyrus, activation of the metabotropic glutamate receptor by the specific agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate, increases release of glutamate in the presence of a low concentration of arachidonic acid. A similar interaction between trans-1-amino-cyclopentyl-1,3-dicarboxylate and arachidonic acid is observed on inositol phospholipid turnover and on protein kinase C activity. We report here that when long-term potentiation is induced in the dentate gyrus by high frequency tetanic stimulation to the perforant path, the synergism between arachidonic acid and trans-1-amino-cyclopentyl-1,3-dicarboxylate is occluded. The occlusion of the synergistic action between arachidonic acid and trans-1-amino-cyclopentyl-1,3-dicarboxylate on glutamate release extended to occlusion of the effect in inositol phospholipid turnover and protein kinase C activation in synaptosomes prepared from dentate gyrus in which long-term potentiation was induced in vivo. One interpretation of the results presented here is that tetanic stimulation is followed by stimulation of metabotropic glutamate receptors at a time when arachidonic acid concentration in the synaptic region is elevated, and that this interaction triggers the presynaptic changes required for expression of long-term potentiation.

Animals↗

PubMed1994

A study of the synergism between metabotropic glutamate receptor activation and arachidonic acid in the rat hippocampus.

We report that activation of the metabotropic glutamate receptor by the specific agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD), increases release of glutamate only in the presence of a low concentration of arachidonic acid (AA). To identify the molecular mechanism underlying this effect, cAMP accumulation, inositol phospholipid metabolism and protein kinase C (PKC) activation were examined in synaptosomes prepared from hippocampus. ACPD increased cAMP accumulation, but this increase was not further enhanced in the presence of AA. ACPD and AA stimulated both inositol phospholipid turnover and PKC activity; a synergistic action was indicated by the additional stimulation in the presence of both agents. The increase in PKC activity, either directly, or indirectly by increased inositol phospholipid turnover, might therefore underlie the enhanced glutamate release.

Animals↗

PubMedDate not supplied

Interleukin-1 beta inhibits glutamate release in hippocampus of young, but not aged, rats.

The proinflammatory cytokine, interleukin-1, is synthesized in neuronal and glial cells and is released in response to stress/injury. IL-1 exerts profound effects on the central nervous system, which include an inhibitory effect on synaptic activity in hippocampus, a brain area expressing a high density of IL-1 receptors. We report that IL-1 beta has an inhibitory effect on KCl-stimulated release of glutamate and KC1-stimulated [45Ca] influx in synaptosomes prepared from hippocampus of 4-month-old rats. These effects were inhibited by the endogenous receptor antagonist, IL-1ra, and by the phospholipase A2 (PLA2) inhibitor, quinacrine, suggesting that IL-1 receptor activation is coupled to PLA2. An inhibitory effect of IL-1 beta on protein kinase C activity was also observed. KC1-induced calcium-dependent release and calcium influx, and protein kinase C activity were significantly decreased in hippocampal synaptosomes prepared from 22-month-old compared to 4-month-old animals. In contrast to the inhibitory effect of IL-1 beta in synaptosomes prepared from young adult animals, no effect was observed on release, calcium influx, or protein kinase C activity in synaptosomes prepared from aged animals. We report that there is an age-related increase in expression of IL-1 beta in hippocampus and propose that this change may underlie the attenuated responses to IL-1 beta in hippocampus of aged animals.

Age Factors↗

PubMedDate not supplied

Training in the Morris water maze occludes the synergism between ACPD and arachidonic acid on glutamate release in synaptosomes prepared from rat hippocampus.

We report here that release of glutamate, inositol phospholipid metabolism, and protein kinase C (PKC) activity are increased in synaptosomes prepared from hippocampi of rats that had been trained in a spatial learning task. In hippocampi obtained from animals that were untrained, activation of the metabotropic glutamate receptor by the specific agonist trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD) increased release of glutamate but only in the presence of a low concentration of arachidonic acid. A similar interaction between arachidonic acid and ACPD was observed on inositol phospholipid turnover and on PKC activity. However, the synergistic effect of arachidonic acid and ACPD on glutamate release was occluded in hippocampal synaptosomes prepared from trained rats. Occlusion of the effect on inositol phospholipid turnover and PKC activation was also observed. These data suggest that the molecular changes that underlie spatial learning may include activation of metabotropic glutamate receptors in the presence of arachidonic acid and that the interaction between arachidonic acid and ACPD triggers the presynaptic changes that accompany learning.

Animals↗