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M A Lynch

Publications and source records attributed to M A Lynch.

At least 55 records · Page 3Linked to original sources
PubMed1998

LTP occludes the interaction between arachidonic acid and ACPD and NGF and ACPD.

We compared the interaction between the metabotropic glutamate receptor agonist ACPD and arachidonic acid with the interaction between ACPD and nerve growth factor (NGF) on presynaptic function in hippocampus. ACPD interacted with both NGF and arachidonic acid to increase KCl-stimulated endogenous glutamate release and calcium concentration in synaptosomes prepared from whole hippocampus and synaptosomes prepared from untetanized dentate gyrus. The data indicate that prior induction of long-term potentiation (LTP) in perforant path granule cells synapses occluded the interaction between ACPD and both NGF and arachidonic acid, suggesting that these agents may play a role in the generation of LTP in dentate gyrus.

Animals↗
PubMed1998

Mutational analysis of the transforming growth factor beta receptor type II gene in human ovarian carcinoma.

In the present study, we evaluated a series of sporadic ovarian carcinomas for mutations within the entire coding region of TbetaR-II. Using reverse transcription-PCR and "Cold" single-strand conformational polymorphism analysis, 6 of 24 samples (25%) were found to contain code-altering mutations in TbetaR-II: (a) four mutations resulting in amino acid substitutions in the highly conserved serine/threonine kinase domain; (b) one mutation resulting in a conservative amino acid change in the transmembrane domain; and (c) a 1-bp insertion in the polyadenylic acid microsatellite region resulting in a reading frameshift. In addition, six cases (25%) exhibited a common bp substitution (C-->T at nucleotide 1322) in both tumor and patient-matched normal tissues. This is the first report of such TbetaR-II mutations in primary human ovarian carcinomas. Immunohistochemical analysis demonstrated a loss of expression of TbetaR-II in 5 of 22 available tumors (23%; 4 of which also had mutations in the coding region) and decreased expression of TbetaR-II in 10 of 22 available tumors (44%; 1 of which had a mutation in the coding region). Thus, the loss or decreased expression of TbetaR-II seems to be a common event in sporadic ovarian carcinomas, and mutational inactivation, due to either frameshift mutations in the polyadenylic acid microsatellite region or point mutations in conserved functional domains, is one mechanism by which this occurs.

Adult↗
PubMed1998

Evidence for a role for synaptophysin in expression of long-term potentiation in rat dentate gyrus.

Maintenance of long-term potentiation in perforant path-granule cell synapses is accompanied by increased glutamate release. Here we investigate the role of synaptophysin in release and in expression of long-term potentiation in dentate gyrus. We report that long-term potentiation was accompanied by increased endogenous glutamate release and increased tyrosine phosphorylation of synaptophysin, but these changes were attenuated when long-term potentiation was inhibited by the tyrosine kinase inhibitor tyrphostin AG879 or by the NMDA antagonist D-aminophosphonovalerate. In vitro analysis revealed that KCl-induced glutamate release was abolished in synaptosomes prepared in the presence of antisynaptophysin. The data suggest a role for synaptophysin in release and indicate that activation of tyrosine kinase and synaptophysin phosphorylation contribute to long-term potentiation perhaps by modulating glutamate release.

Animals↗
PubMed1998

Biphasic modulation of intracellular Ca2+ concentration by interleukin-1beta in cortical synaptosomes: involvement of a pertussis toxin-sensitive G-protein and mitogen-activated protein kinase.

The modulation of intracellular Ca2+ concentration ([Ca2+]i) by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) was assessed in synaptosomes loaded with the Ca2+-sensitive dye, Fura-2AM. IL-1beta was found to exert a biphasic effect on the KCl-induced rise in [Ca2+]i, extending an inhibitory effect at lower (3.5 ng/ml) concentrations, and a stimulatory effect at high (100 ng/ml) concentrations. The inhibitory action of IL-1beta on [Ca2+]i was sensitive to pertussis toxin (PTX; 2 microg/ml), indicating a role for a PTX-sensitive G-protein, but was unaffected by the p42 mitogen-activated protein kinase kinase (MAP kinase kinase) inhibitor, PD 098059 (2 microM). In contrast, the stimulatory action of higher concentrations of IL-1beta on [Ca2+]i was blocked by PD 098059 and unaffected by PTX. We conclude that the biphasic actions of IL-1beta on the KCl-induced rise in [Ca2+]i are mediated through activation of alternative second messenger pathways.

Animals↗
PubMed1998

Dietary supplementation with vitamin E reverses the age-related deficit in long term potentiation in dentate gyrus.

Long term potentiation (LTP) in dentate gyrus is impaired in aged rats, and this has been associated with an age-related decrease in membrane arachidonic acid concentration. In this study, we considered whether the trigger for this age-related decrease in arachidonic acid might be increased lipid peroxidation stimulated by the proinflammatory cytokine, interleukin-1beta. Groups of aged and young rats were fed on a control diet or a diet supplemented with alpha-tocopherol and assessed for their ability to sustain LTP. Aged rats fed on the control diet exhibited an impaired ability to sustain LTP and analysis of tissue prepared from these rats exhibited increased interleukin-1beta, increased lipid peroxidation, and decreased membrane arachidonic acid concentration compared with young rats fed on either diet. Aged rats fed on the supplemented diet sustained LTP in a manner indistinguishable from young rats, and the age-related increases in interleukin-1beta and lipid peroxidation and the decrease in membrane arachidonic acid concentration were all reversed. We propose that interleukin-1beta may be the trigger that induces these age-related changes and may therefore be responsible for the deficit in long term potentiation in aged rats. The observation that alpha-tocopherol reverses these changes is consistent with the hypothesis that some age-related changes in hippocampus might derive from oxidative stress.

Aging↗
PubMed1998

Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation.

Several cytokines and their receptors are identified in brain; one of these is the proinflammatory cytokine interleukin-1beta that is synthesized and released from neurons and glia in response to stress or insult. Among the actions of interleukin-1beta is its ability to inhibit long-term potentiation in the hippocampus in vitro, an action that mimics one of the consequences of stress and age. It has been shown that the concentration of interleukin-1beta in brain tissue is increased in neurodegenerative conditions, and recent evidence from our laboratory has indicated an increase in the concentration of interleukin-1beta in the hippocampus of aged rats. These observations led us to consider that the underlying common cause of impaired long-term potentiation in aged and stressed rats might be increased endogenous interleukin-1beta concentration in hippocampus. The data presented here indicate that there was an inverse relationship between concentration of interleukin-1beta in the dentate gyrus and long-term potentiation in perforant path-->granule cell synapses in aged rats, stressed rats, and rats pretreated with interleukin-1beta. The evidence suggested that the cytokine induces formation of reactive oxygen species that triggers lipid peroxidation in vivo, as well as in vitro, and that these changes lead to depletion of membrane arachidonic acid that correlates with impaired long-term potentiation. We propose that three theories of aging, the glucocorticoid theory, the membrane theory, and the free radical theory, constitute three facets of age with one underlying trigger: an increase in the endogenous concentration of interleukin-1beta in hippocampus.

Adrenal Cortex Hormones↗
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

Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1 beta?

Ageing is associated with impairments in a variety of biological functions, one of the most striking might be considered to be the impairment in cognitive function. This impairment probably relates to the vulnerability of the hippocampus to the ageing process, since several cognitive functions rely on the integrity of this brain area. Analysis of the mechanisms underlying the effect of ageing on hippocampal function has focused to a great extent on analysis of age-related changes in long-term potentiation (LTP) in hippocampus of experimental animals. LTP is a remarkable form of synaptic plasticity which is characterized by a persistent increase in synaptic efficacy following tetanic stimulation of an afferent pathway to one of the hippocampal subfields. On the basis of its properties, LTP has been proposed as a biological substrate for learning and/or memory. There is general agreement that aged rats exhibit an impaired ability to sustain LTP but there is no agreement on the underlying cause of this deficit. In this review, the evidence which suggests that age-related changes in membrane composition, triggered by oxidative changes, might significantly contribute to the impairment in LTP, is considered. These findings are supported by recent data which indicates that dietary supplementation with the antioxidant vitamins, E and C, reversed the age-related impairment in LTP, in parallel with reversing the age-related decrease in alpha-tocopherol concentration and the age-related increase in lipid peroxidation. The possibility that the proinflammatory cytokine, interleukin-1 beta, triggers several age-related changes in hippocampus is considered and, based on the evidence presented, the hypothesis that interleukin-1 beta plays a significant role in ageing in the hippocampus is proposed.

Aging↗
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

Changes in protein synthesis and synthesis of the synaptic vesicle protein, synaptophysin, in entorhinal cortex following induction of long-term potentiation in dentate gyrus: an age-related study in the rat.

We have examined protein synthesis in entorhinal cortex following induction of long-term potentiation (LTP) in perforant path-granule cell synapses. The data presented here indicate that there was an increase in [35S]methionine labelling of TCA-precipitated proteins and [35S]methionine labelling of synaptophysin in the ipsilateral entorhinal cortex 40 min after induction of LTP in dentate gyrus. Intraventricular injection of both the NMDA antagonist, D-amino-phosphonovalerate, and the protein synthesis inhibitor, anisomycin reduced protein synthesis though the decrease caused by anisomycin was much more profound. Both agents blocked induction of LTP and the increase in protein synthesis and synaptophysin synthesis which accompanied LTP. These data indicate a close coupling of increased protein synthesis in the entorhinal cortex and expression of LTP in the dentate gyrus. This coupling was further suggested by the absence of an LTP-associated increase in protein synthesis in aged animals, in which LTP was markedly attenuated. The possibility that these changes impact on morphological changes which accompany LTP is discussed.

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↗