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Biomedical subjects

G Lynch

Publications and source records attributed to G Lynch.

At least 307 records · Page 17Linked to original sources
PubMed1990

Role of NMDA and non-NMDA receptors in synaptic transmission in rat piriform cortex.

The pharmacology of synaptic transmission was studied in slices of rat piriform cortex using the selective non-NMDA glutamate receptor antagonist 6.7-dinitroquinoxaline-2,3-dione (DNQX) and the selective NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5). DNQX produced a dose-dependent blockade of synaptic transmission at both lateral olfactory tract and associational system synapses with half-maximal effects at about 2.5 microM. D-AP5 had no significant effects on field potentials recorded in medium containing 2.5 mM Mg++. However in low Mg++ (100-200 microM) medium, D-AP5 did reduce a slow component of postsynaptic responses in both synaptic systems. In Mg(++)-free medium, 20 microM DNQX did not completely block transmission; the remaining response components were blocked by D-AP5. These results suggest that normal synaptic transmission in the two main inputs to the superficial layers of piriform cortex is mediated by non-NMDA receptors but that NMDA receptors can also participate under conditions where the Mg++ block of the NMDA channel is alleviated.

2-Amino-5-phosphonovalerate↗
PubMed1990

Reversed intestinal rotation associated with anomalous mesenteric venous drainage. Report of a case.

Reverse intestinal rotation is a congenital abnormality of midgut rotation. Mesenteric arterial, venous, and lymphatic compression may occur, but associated anomalous mesenteric venous drainage is extremely rare. The case presented illustrates the importance of recognition of intestinal malrotation and the danger of bowel resection in the presence of anomalous mesenteric venous drainage.

Adult↗
PubMed1990

Induction of ornithine decarboxylase by subseizure stimulation in the hippocampus in vivo.

Electrical stimulation of the Schaffer-collateral axonal system under conditions which do not elicit detectable seizure activity causes an increase in the activity of ornithine decarboxylase (ODC), the rate limiting enzyme of polyamine synthesis, in the hippocampus, olfactory cortex, neocortex and olfactory bulb. The degree of ODC activation is dependent upon the stimulus parameters. The results support the hypothesis that neuronal activity regulates hippocampal polyamine concentrations.

Animals↗
PubMed1990

Activation of the glycine site associated with the NMDA receptor is required for induction of LTP in neonatal hippocampus.

The role played by the glycine site associated with the NMDA receptor in inducing long-term potentiation (LTP) in neonatal hippocampus was examined. An antagonist of the glycine site, 7-chlorokynurenic acid (Cl-Kyn), completely blocked both the short-term and the long-term potentiation associated with theta burst stimulation (TBS) linked to NMDA receptor activation in slices from hippocampus at postnatal days 10-16; this effect was reversed by the glycine agonist, D-serine. Analysis of the TBS-evoked responses showed: (1) a developmental alteration in the burst response morphology that may be related to maturation of GABA-mediated inhibition; and (2) that, unlike 2-amino-5-phosphonovalerate (AP5), Cl-Kyn did not reduce any portion of the burst response. These results suggest that stimulation of the glycine site coupled to the NMDA receptor complex is necessary to induce LTP in neonatal tissue and that two NMDA receptor types may be present in the hippocampus.

Animals↗
PubMed1990

The nature and causes of hippocampal long-term potentiation.

One of the most fascinating features of the hippocampus is its capacity for plasticity. Long-term potentiation (LTP), a stable facilitation of synaptic potentials after high-frequency synaptic activity, is very prominent in hippocampus and is a leading candidate memory storage mechanism. Here, we discuss the nature and causes of LTP and relate them to endogenous rhythmic neuronal activity patterns and their potential roles in memory. Anatomical studies indicate that LTP is accompanied by postsynaptic structural modifications while pharmacological studies strongly suggest that LTP is not due to an increase in presynaptic transmitter release. In field CA1, LTP induction appears to be triggered by a postsynaptic influx of calcium through NMDA receptor-linked channels. Possible roles of several calcium-sensitive enzyme systems in LTP are discussed and it is argued that activation of a calcium-dependent protease (calpain) could produce the structural changes linked to LTP. Rhythmic bursting activity is highly effective in inducing LTP and it is argued that the endogenous hippocampal theta rhythm plays a role in LTP induction in vivo. Finally, studies indicate that LTP and certain types of memory share a common pharmacology and the use of electrical brain stimulation as a sensory cue suggests that LTP develops when the significance of that cue is learned.

Action Potentials↗
PubMed1990

Protein kinase C activity is not responsible for the expression of long-term potentiation in hippocampus.

Long-term potentiation (LTP) in hippocampus has been proposed to result from a tonic activation of protein kinase C. This hypothesis predicts that stimulation of the kinase would produce a smaller change in response size on potentiated versus control pathways and, conversely, that inhibition of the kinase would reduce potentiated inputs to a greater degree than control responses. We tested these predictions using phorbol esters to activate and using the antagonist H-7 to inhibit protein kinase C; we found that the actions of these drugs on synaptic transmission were not affected by prior induction of LTP. Both compounds, however, significantly decreased the contribution of N-methyl-D-aspartate receptors to synaptic potentials, a result that accounts for the suppressive effects of these compounds on LTP formation. Thus protein kinase C is probably not involved in the expression of LTP but may play a role in the receptor-mediated events participating in its induction.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

Levels of mRNA for a putative kainate receptor are affected by seizures.

In situ hybridization and RNA blot-hybridization techniques were used (i) to examine the regional distribution of mRNA for a putative kainate receptor in adult rat brain and ii) to test the possibility that seizures affect expression of the receptor gene. The highest densities of hybridization were distributed within hippocampal pyramidal and granule cells, medial habenula, Purkinje cells and the molecular layer of cerebellum, and olfactory bulb. Recurrent limbic seizures caused a massive, delayed, and reversible reduction in levels of the kainate receptor mRNA in dentate gyrus; lesser decreases were found in pyramidal cell fields of hippocampus and superficial cortex. These findings provide evidence that unusual patterns of physiological activity can alter genomic expression for a subclass of glutamate receptors in brain.

Animals↗
PubMed1990

N-Methyl-D-aspartate and quisqualate/DL-alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors: differential regulation by phospholipase C treatment.

The effect of phospholipase C (PLC) treatment of rat brain membranes on the binding properties of excitatory amino acid receptors was investigated using both a phosphsphatidylcholine-hydrolyzing PLC from Clostridium perfringens and a phosphatidylinositol-specific PLC from Bacillus thuringiensis. PLC from C. perfringens produced an increased affinity of the quisqualate/DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor for its ligand, whereas kainate receptor binding was not affected. Both kinetic analysis and equilibrium saturation experiments indicated that PLC treatment produced a decrease in affinity for [3H]N-(1-[thienyl]cyclohexyl)-piperidine [( 3H]TCP), a ligand for the N-methyl-D-aspartate (NMDA) receptor-associated ionic channel, when the channel was fully activated by high concentrations of glutamate and glycine but increased its binding under conditions in which the channel was presumably closed. This latter component of the binding was not due to an interaction of [3H]TCP with non-glutamate receptor sites, such as sigma opioid and histamine H3 receptors. Binding of [3H]glutamate and [3H] glycine to the NMDA receptors was not modified by PLC treatment, but there was a large decrease in the binding of the NMDA antagonist [3H]3-[(+/-)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid. Stimulation by glycine of [3H]glutamate binding was also abolished following PLC treatment. In contrast to PLC from C. perfringens, phosphatidylinositol-specific PLC treatment did not detectably modify the binding properties of the quisqualate/AMPA receptor or the NMDA receptor channel. These data indicate that alterations in the lipid microenvironment of the glutamate receptors modulate both the conformation and the function of the receptors and suggest a possible role for phospholipases in the regulation of synaptic transmission at excitatory synapses.

Animals↗
PubMed1989

The protease inhibitor leupeptin interferes with the development of LTP in hippocampal slices.

The effect of leupeptin, an inhibitor of thiol-proteases, was tested on the induction of long-term potentiation (LTP) in field CA1 of hippocampal slices. Two h of drug application did not produce substantial changes while a greater than 3-h application caused a sizeable reduction in the degree of LTP induced. Leupeptin had no obvious effects on the facilitation of postsynaptic responses occurring within or between the short high frequency bursts used to induce LTP, suggesting that the drug acted on cellular chemistries occurring after the initial physiological events that normally trigger LTP. These results are consistent with the hypothesis that a calcium-activated thiol protease (calpain) is involved in the induction of LTP.

Action Potentials↗
PubMed1989

Proteolytic conversion of xanthine dehydrogenase to xanthine oxidase: evidence against a role for calcium-activated protease (calpain).

The present study tested the hypothesis that calpain is responsible for the limited proteolytic conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO). We compared the effects of various proteases on the activity and molecular weight of a purified preparation of xanthine dehydrogenase from rat liver. In agreement with previous reports, trypsin treatment produced a complete conversion of XD to XO accompanied by a limited proteolysis of XDH from an Mr of 140 kD to an Mr of 90 kD. Treatment with calpain I or calpain II did not produce a conversion from XD to XO nor did it result in partial proteolysis of the enzyme. Similarly, trypsin treatment partially degraded a reversibly oxidized form of xanthine dehydrogenase while calpain I or calpain II were ineffective. The possibility that an endogenous inhibitor prevented the proteolysis of XDH by calpain I or II was excluded by verifying that brain spectrin, a known calpain substrate, was degraded under the same incubation conditions. The results indicate that calpain is not likely to be responsible for the in vivo conversion of XD to XO under pathological conditions.

Animals↗
PubMed1989

Developmental changes in synaptic properties in hippocampus of neonatal rats.

The properties of synaptic responses in area CA1 of hippocampus were analyzed in slices prepared from 7-9 and 12-15 day old neonate rats. As expected from earlier work, only slices of two-week-old animals showed a consistent degree of long-term potentiation (LTP) in response to patterned high frequency stimulation. Several other synaptic properties were found to change during this developmental period. Inhibitory responses were absent in 7-9 day old but not in 12-15 day old neonates. Paired-pulse facilitation and the calcium sensitivity of postsynaptic responses were considerably reduced in 7-9 as compared to 12-15 day old rats. However, phorbol esters and 4-aminopyridine treatment still produced a strong facilitation of field potentials. The N-methyl-D-aspartate (NMDA) component of responses to single pulse stimulation in low magnesium medium was found to be larger in slices of 7-9 than 12-15 day old or adult animals. At the two time periods examined, trains of high frequency stimulation applied in the presence of regular magnesium elicited an NMDA dependent response. It is concluded that the differences in synaptic properties observed between 7-9 and 12-15 day old neonates may not account for the absence of LTP in the younger animals.

Action Potentials↗
PubMed1989

Ischemia triggers NMDA receptor-linked cytoskeletal proteolysis in hippocampus.

Transient forebrain ischemia is followed within minutes by accelerated proteolysis of the cytoskeletal protein, spectrin. This effect is most pronounced in the selectively vulnerable CA1 region of hippocampus which also experiences a second proteolytic phase during the terminal stages of neuronal degeneration. Both proteolytic phases are suppressed by MK-801, an NMDA receptor antagonist. Cytoskeletal disruption, via NMDA receptor-linked proteolytic events, is suggested to predispose vulnerable neurons to delayed cell death.

Animals↗
PubMed1989

Quinoxaline derivatives are high-affinity antagonists of the NMDA receptor-associated glycine sites.

Membranes from rat telencephalon contain strychnine-insensitive glycine binding sites associated with NMDA receptors. Three quinoxaline derivatives, among them the high-affinity AMPA receptor antagonists CNQX and DNQX, were found to inhibit [3H]glycine binding to these sites with micromolar affinities. Binding of these compounds to the glycine site also inhibited glutamate-stimulated association and dissociation of [3H]TCP. This suggests that these AMPA antagonists, like the structurally related compound kynurenate, act as glycine site antagonists.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1989

Theta pattern stimulation and the induction of LTP: the sequence in which synapses are stimulated determines the degree to which they potentiate.

Induction of long-term potentiation (LTP) by asynchronous stimulation of converging afferents was studied in hippocampal slices. Three stimulation electrodes were positioned to activate separate groups of Schaffer-commissural inputs to a population of CA1 pyramidal cells. Patterned stimulation consisted of a single coincident priming pulse to all 3 electrodes followed by a burst of 4 pulses (100 Hz) to the first input (S1) at a delay of 180 ms, to the second (S2) at a delay of 200 ms, and to the third (S3) at a delay of 220 ms. This pattern was repeated 10 times at 5-s intervals. The magnitude of LTP induced (measured 20 min after stimulation) was greatest for the first stimulated input, intermediate for the second, and least for the third. Intracellular recordings indicated that the greatest postsynaptic depolarization occurred during the period of S2 stimulation; thus the magnitude of LTP induced was not simply dependent on the degree of depolarization during afferent activation. Rather, sustained depolarization after synaptic activation could contribute to LTP induction by prolonging the activity of N-methyl-D-aspartate receptor-gated channels. Earlier-arriving bursts may also trigger an inhibitory process that reduces the effectiveness of later bursts for inducing LTP.

Action Potentials↗
PubMed1989

Evidence that changes in presynaptic calcium currents are not responsible for long-term potentiation in hippocampus.

We used two approaches to test the possibility that changes in presynaptic calcium currents might be responsible for the long-term potentiation (LTP) effect induced by high-frequency stimulation in area CA1 of hippocampal slices. In a first series of experiments, we compared the effect of LTP induction on paired-pulse facilitation with that produced by changes in extracellular calcium concentration, a procedure that modifies presynaptic calcium currents during depolarization by changing the ionic gradient for calcium. In hippocampus, as in peripheral synapses, increasing concentrations of extracellular calcium caused a marked reduction in the degree of facilitation obtained with paired-pulse stimulation; LTP, conversely, did not affect the facilitation ratio. The differential effect of changing calcium concentrations versus LTP induction on paired-pulse facilitation was observed with different interpulse intervals as well as in conditions in which the changes in response size produced by the two manipulations were comparable. In the second approach, we measured calcium dependency curves of synaptic responses before and after LTP induction or application of 4-aminopyridine, a blocker of potassium channels that increases presynaptic calcium currents by slowing spike repolarization. Procedures that increase calcium entry into terminals during transmission should shift to the left the sigmoidal function relating extracellular calcium to the slope of the extracellular response. This in turn should result in disproportionate effects of the procedure as a function of the calcium concentration. This prediction was realized with 4-aminopyridine but did not occur following LTP induction: control and potentiated responses were similarly affected by changes in calcium concentration. Although indirectly, these data strongly suggest that LTP is not accompanied by alterations in the presynaptic calcium dynamics associated with transmitter release.

Action Potentials↗
PubMed1989

The NMDA receptor-mediated components of responses evoked by patterned stimulation are not increased by long-term potentiation.

The participation of N-methyl-D-aspartate (NMDA) receptors in synaptic transmission before and after induction of long-term potentiation (LTP) was studied in field CA1 of hippocampal slices. NMDA receptor-mediated postsynaptic responses were determined by comparing responses recorded in the presence and absence of the selective antagonist, D-2-amino-5-phosphonopentanoate (D-AP5, 50 microM). In the presence of physiological magnesium concentrations (1 mM), robust D-AP5-sensitive responses could be evoked by high frequency bursts (4 pulses, 100 Hz) when burst stimulation was preceded 200 ms earlier by 'priming' stimulation (2 pulses, 15 ms apart) of a separate input. Induction of LTP resulted in a substantial potentiation (35%) of non-NMDA-mediated responses to primed bursts but not of NMDA-mediated responses. These results suggest that long-term postsynaptic modifications are at least partly responsible for the expression of LTP.

Animals↗