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Biomedical subjects

G Lynch

Publications and source records attributed to G Lynch.

At least 415 records · Page 23Linked to original sources
PubMed1982

The regulation of pyruvate dehydrogenase activity in rat hippocampal slices: effect of dichloroacetate.

The effects of dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, on the phosphorylation of the alpha-subunit of pyruvate dehydrogenase and on the activity of pyruvate dehydrogenase (pyruvate:lipoamide oxidoreductase (decarboxylating and acceptor-acetylating), EC 1.2.4.1, PDH) were investigated in rat hippocampal slices. Incubating hippocampal slices with increasing concentrations of DCA resulted in an increase in the active portion of PDH, without changes in the total PDH activity, as well as an increase in the in vitro phosphorylation of alpha-PDH. The effect of DCA on PDH activity was very rapid, being almost maximal after 5 min. These results indicate that DCA in the hippocampal slice preparation inhibits PDH kinase and consequently stimulates PDH activity by decreasing its endogenous state of phosphorylation. Moreover the time-course of the effect of DCA suggests that the turnover rate of the phosphate group carried by alpha-PDH is very rapid and can be manipulated by altering PDH kinase activity.

Acetates↗
PubMed1982

Entorhinal cortex lesions induce a decreased calcium transport in hippocampal mitochondria.

Lesions to the entorhinal afferent of the hippocampus in rats caused marked changes in calcium transport into mitochondria. Pyruvate-supported calcium transport into mitochondria from the denervated hippocampus was decreased to a larger extent than succinate-supported transport, and adenosine triphosphate-supported transport was not significantly modified. Although cytochrome oxidase and succinate dehydrogenase activities were not significantly changed by entorhinal lesions, pyruvate flux through pyruvate dehydrogenase was significantly decreased, and this effect was correlated with changes in pyruvate-supported calcium transport. The active portion of pyruvate dehydrogenase decreased, whereas total pyruvate dehydrogenase was not modified. These data suggest that denervation might initiate dendritic atrophy and subsequent growth responses by modifying calcium regulation through a change in the phosphorylation of pyruvate dehydrogenase.

Adenosine Triphosphate↗
PubMed1982

A combined in vivo/in vitro study of the presynaptic release of adenosine derivatives in the hippocampus.

To investigate the release of adenine compounds from defined neuronal pathways, we employed a hippocampal slice preparation in which a selective-loading of the releasable pools was achieved in vivo with the aid of axonal transport. By injecting radioactive adenosine stereotaxically into the entorhinal cortex, the major afferent system to the dentate gyrus (the perforant path) was loaded within 20-36 h, at which time the rats were killed and hippocampal slices were prepared. The efflux of radioactive material, as recovered from the perfusate and measured in a scintillation counter, was found to be significantly increased in response to electrophysiologically controlled stimulation of the perforant path but not to stimulation of an alternative fiber tract, the fimbria. These findings provide supportive and more direct evidence for an activation-coupled release of adenosine derivatives from presynaptic sites in the central nervous system.

Adenosine↗
PubMed1982

The blocking action of baclofen on excitatory transmission in the rat hippocampal slice.

The mode of action of baclofen on the physiology of the rat hippocampus was investigated by studying its effect on electrophysiological responses in the hippocampal slice preparation and by measuring biochemical parameters related to glutamate uptake, binding, and release. Baclofen inhibited, in a dose-dependent fashion, the dendritic field potentials in field CA1 produced by stimulation of the Schaffer commissural fiber system. The drug was inactive in this respect at concentrations of 10 and 100 nM but consistently reduced the amplitude of both the dendritic field potential and the population spike at a concentration of 1 microM. At a concentration of 25 microM, baclofen virtually abolished the dendritic and cell body responses to afferent stimulation. Recovery of field potentials required between 7 and 10 min following the addition of 1 microM baclofen. The levorotatory form of baclofen was much more potent in suppressing synaptic responses than was the dextrorotatory enantiomer. Baclofen, at a concentration of 5 microM, strongly antagonized the excitation of pyramidal neurons evoked by iontophoretically applied glutamate. The antagonism of the glutamate effect was much reduced when the slices were maintained in low calcium, high magnesium perfusion medium. Moreover, under low calcium conditions, baclofen did not interfere with the effects of bath-applied glutamate on antidromically elicited responses. Baclofen did not affect the Na+-dependent or Na+-independent binding of [3H]glutamate to crude synaptic membrane fractions from the hippocampus. However, at a concentration of 1 microM, it markedly inhibited potassium-induced release of [3H]glutamate from hippocampal synaptosomes. Taken together, the present results strongly suggest that baclofen suppresses synaptic responses in the Schaffer commissural fiber system of the hippocampus by blocking the release of an excitatory amino acid transmitter.

Action Potentials↗
PubMed1982

Phase II evaluation of DON (6-diazo-5-oxo-L-norleucine) in patients with advanced colorectal carcinoma.

Twenty-three patients with advanced colorectal carcinoma, previously treated with chemotherapy, were entered in a phase II trial of DON (6-Diazo-5-Oxo-L-Norleucine), an antagonist of L-glutamine. One of 14 adequately treated patients had a partial response of 6 weeks duration. The dose-limiting toxicity was nausea and vomiting; 48% of patients originally entered on the study withdrew because of vomiting. Myelosuppression was minimal, with only mild thrombocytopenia noted. The dose and schedule used in this study were beyond the maximally tolerated dose for many patients; future phase II studies of DON will be difficult to complete unless schedules and doses are found which result in less nausea and vomiting.

Adult↗
PubMed1981

Increased [3H]glutamate receptor binding in aged rats.

Na-independent [3H]glutamate binding to rat hippocampal membranes increases progressively as a function of age. The increased binding represents an increased number of binding sites without changes in their apparent affinity for glutamate. However, [3H]glutamate binding, measured with a saturating concentration of calcium does not change at various ages. This does not reflect a change in the apparent affinity of calcium ions to stimulate [3H]glutamate binding, but a decrease in their maximal stimulatory effect. These results are discussed in relationship to age-related changes in certain physiological and behavioral functions.

Aging↗
PubMed1981

Hippocampal glutamate receptors.

For years, the hippocampus has been the privileged domain of anatomists and electrophysiologists for investigating various neurobiological processes. The present review deals with recent work which shows that this structure is also well suited to study the role of glutamate as a neurotransmitter and more particularly the characteristics of glutamate receptors and their possible involvement in hippocampal function. After a brief description of the main anatomical features of the hippocampus, we attempt a critical evaluation of the electrophysiological studies of hippocampal glutamate receptors. We then describe the properties of Na-independent 3H-glutamate binding sites in hippocampal membranes, and discuss the possibility that these binding sites are related to postsynaptic glutamate receptors. Finally we show that these binding sites are extremely labile and that hippocampal membranes possess various mechanisms which regulate their number. In particular we develop the idea that the calcium-stimulation of 3H-glutamate binding in hippocampal membranes may be the mechanism by which electrical activity regulates the number of glutamate receptors at hippocampal synapses and thus induces long-lasting changes in synaptic transmission.

Animals↗
PubMed1981

Evidence that the 40,000 Mr phosphoprotein influenced by high frequency synaptic stimulation is the alpha subunit of pyruvate dehydrogenase.

We have previously shown that brief periods of high frequency synaptic stimulation of the rat hippocampus influence the endogenous phosphorylation of a 40,000 Mr brain protein (Browning et al.). The results of the present study demonstrate that this brain phosphoprotein is enriched in a purified mitochondrial fraction and co-migrates with the alpha-subunit of pyruvate dehydrogenase in sodium dodecyl sulfate polyacrylamide gels. Comparisons of total and partial proteolytic fingerprints indicate that the two proteins are essentially identical. In addition, the phosphorylation of the 40,000 Mr brain protein is sensitive to both dichloroacetate and magnesium as has been reported for pyruvate dehydrogenase. Taken together these data provide persuasive evidence that the brain protein is the alpha-subunit of pyruvate dehydrogenase and thereby raise the possibility that even very short periods of synaptic activity influence an enzyme of particular importance to mitochondrial metabolism in brain.

Animals↗
PubMed1981

Sprouting in the hippocampus is accompanied by an increase in coated vesicles.

Coated vesicles within dentate gyrus granule cell dendrites were found free in the cytoplasm and also attached to the smooth endoplasmic reticulum and plasmalemma. Coated vesicles began increasing in number 40-48 h following partial dendritic deafferentation. This increase continued up to 15-30 days postlesion, after which the population steadily declined to control values. These results combined with the findings of previous studies suggest an involvement of coated vesicles in synaptic reinnervation.

Animals↗
PubMed1981

Development of glutamate binding sites and their regulation by calcium in rat hippocampus.

The postnasal development of the Na-independent [3H]glutamate binding sites, which exhibit some characteristics of postsynaptic glutamate receptors, has been studied in rat hippocampal membranes. The amount of binding sites (expressed in pmol/hippocampus) represents 4% of the adult level at postnatal day (PND) 4, increases very rapidly until PND 9, and then increases at a slower rate reaching 80% of the adult value at PND 23. In contrast, the density of binding sites (expressed in pmol/mg protein) exhibits a maximum at PND 9 and slowly decreases to reach the adult value at PND 23. These changes seen to be only quantitative since the affinity (about 450nM) and Hill coefficient (about 1.0) of these binding sites remain constant throughout development. Calcium ions have been shown to markedly stimulate [3H]glutamate binding in adult hippocampal membranes. This effect appears on PND 9--10 and increases rapidly until PND 16 when it is similar to that seen in the adult rat. We also determined the minimum age at which long-term potentiation (LTP) of synaptic transmission could be detected in the CA1 field of hippocampal slice preparations following repetitive electrical stimulation of the Schaffer-commissural pathways. LTP was only rarely detected at PND 8 whereas it could be reliably obtained after PND 9. These results indicate that the postnatal development of Na-independent glutamate binding sites closely parallels synapse formation in the hippocampus, further supporting the idea that the binding sites are associated with a physiological receptor. They also show that the appearance of the stimulatory effect of calcium on glutamate binding occurs at a time when several forms of synaptic plasticity appear in the hippocampus. In particular the correlation of the development of LTP with the calcium-stimulation of glutamate binding suggests that these phenomena have similar cellular mechanisms.

Aging↗
PubMed1981

Hippocampal aging in rats: a morphometric study of multiple variables in semithin sections.

Quantitative analyses of pyramidal cells, astrocytes, dark glia (microglia and dark oligodendrocytes), lipofuscin accumulation and astrocyte reactivity were carried out in semithin sections from field CA3 of the hippocampus of rats in 3 age groups (4-7 mo., 13-15 mo., 25-28 mo.). A decrease in neuronal density (approximately 25%) and an increase in dark glia were found in the oldest group. The astrocyte population was stable with age. Lipofuscin increased by 13-15 mo. and increased further by 25-28 mo. Qualitative examples of several kinds of glial reactivity are also described. Our observations indicate that hippocampal changes in aging rats exhibit some similarities to brain changes reported in other mammalian species, and also illustrate the value of semithin sections for examining neuromorphologic correlates of brain aging.

Aging↗
PubMed1981

Characterization of two [3H]glutamate binding sites in rat hippocampal membranes.

The specific binding of L-[3H]glutamate was investigated in the presence and the absence of sodium ions in freshly prepared membranes from rat hippocampus. Sodium ions were found to have a biphasic effect; low concentrations induced a marked inhibition of the binding (in the range 0.5-5.0 mM), whereas higher concentrations resulted in a dose-dependent stimulation of binding (in the range 10-150 mM). These results permit the discrimination of two binding sites in hippocampal membranes. Both Na+-independent and Na+-dependent binding sites were saturable, exhibiting dissociation constants at 30 degrees C of 750 nM and 2.4 microM, respectively, with Hill coefficients not significantly different from unity, and maximal number of sites of 6.5 and 75 pmol/mg protein, respectively. [3H]Glutamate binding to both sites reached equilibrium between 5 and 10 min and was reversible. The relative potencies of a wide range of compounds, with known pharmacological activities, to inhibit [3H]glutamate binding were very different for the Na+-independent and Na+-dependent binding and suggested that the former sites were related to post-synaptic glutamate receptors, whereas the latter were related to high-affinity uptake sites. This conclusion was also supported by the considerable variation in the regional distribution of the Na+-dependent binding site, which paralleled that of the high-affinity glutamate uptake; the Na+-independent binding exhibited less regional variation.

Animals↗