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M L Errington

Publications and source records attributed to M L Errington.

At least 55 records · Page 3Linked to original sources
PubMed1989

Arachidonic acid induces a long-term activity-dependent enhancement of synaptic transmission in the hippocampus.

Long-term potentiation (LTP) is a widely studied model of the synaptic basis of information storage in the mammalian brain. The induction of LTP is triggered by the postsynaptic entry of calcium through the channel associated with the N-methyl-D-aspartate (NMDA) receptor, whereas its maintenance is mediated, at least in part, by presynaptic mechanisms. To explain how postsynaptic events can lead to an increase in transmitter release, we have postulated the existence of a retrograde messenger to carry information from the postsynaptic side of the synapse to recently active presynaptic terminals. Candidates for a retrograde messenger include arachidonic acid or one of its lipoxygenase metabolites. Here we report that weak activation of the perforant path, when given in the presence of arachidonic acid, leads to a slow-onset persistent increase in synaptic efficacy both in vivo and in vitro. The activity-dependent potentiation thus produced is accompanied by an increase in the release of glutamate, and is non-additive with tetanus-induced LTP. These observations indicate a role for arachidonic acid as a retrograde messenger in the later, but not the initial, stages of LTP.

2-Amino-5-phosphonovalerate↗
PubMed1989

The increase in [3H]glutamate release associated with long-term potentiation in the dentate gyrus is blocked by commissural stimulation.

Previous findings have indicated that long-term potentiation (LTP) in the perforant path-granule cell synapses is accompanied by an increase in K+-stimulated, calcium-dependent release of [3H]glutamate 45 min after the induction of LTP. Here we report that release of [3H]glutamate is increased at 3 time intervals following induction of LTP, 2.5 min, 45 min and 3 h. Stimulation of the commissural input to the granule cells blocks the induction of LTP and the increase in [3H]glutamate release.

Animals↗
PubMed1989

Nordihydroguaiaretic acid blocks the synaptic component of long-term potentiation and the associated increases in release of glutamate and arachidonate: an in vivo study in the dentate gyrus of the rat.

The dentate gyrus of anaesthetized rats was perfused with artificial cerebrospinal fluid while field responses evoked by stimulation of the perforant path were monitored. Perfusates were collected for analysis of endogenous glutamate, aspartate and arachidonate. In animals in which long-term potentiation was induced by tetanic stimulation, there was a sustained increase in the concentration of glutamate in the perfusate, and, less reliably, in aspartate, as previously reported by Bliss et al. (J. Physiol., Lond. 377, 391-408, 1986) and Errington et al. (Neuroscience 20, 279-284, 1987). The lipoxygenase and phospholipase A2 inhibitor nordihydroguaiaretic acid, when added to the perfusate 30 min before the tetanus, abolished both long-term potentiation of the population excitatory postsynaptic potential and the tetanus-induced increase in glutamate release. Long-term potentiation of the population spike was reduced but not abolished. There was also a sustained increase in the release of arachidonic acid following the induction of long-term potentiation which did not occur when induction was blocked by nordihydroguaiaretic acid. These results are discussed in the light of the possibility that arachidonic acid or one of its lipoxygenase metabolites may be the retrograde messenger which we have postulated is released from postsynaptic sites following tetanic stimulation to trigger increased transmitter release from presynaptic terminals.

Action Potentials↗
PubMed1988

Long-term potentiation in the dentate gyrus of the anaesthetized rat is accompanied by an increase in protein efflux into push-pull cannula perfusates.

Changes in protein content of push-pull cannula perfusates from the dentate gyrus of anaesthetized rats were analyzed before and after the induction of long-term potentiation (LTP). LTP, induced by either high-frequency stimulation of the perforant path or raising the extracellular calcium concentration, was associated with increases in the protein content of the perfusates. Tetanically induced LTP was accompanied with a large but delayed increase (apparent in the second hour after the stimulation) in protein efflux. In contrast, when LTP was induced by the elevation of extracellular calcium concentration, a smaller but more immediate increase in protein efflux was observed. When 5-D-aminophosphonovalerate was used to block the induction of LTP, no increase was observed in either case. These results indicate that LTP in the dentate gyrus is accompanied by an increase in the efflux of proteins into push-pull cannula perfusates. The possible origins of these proteins and their role in LTP are discussed.

2-Amino-5-phosphonovalerate↗
PubMed1988

Naloxone blocks the induction of long-term potentiation in the lateral but not in the medial perforant pathway in the anesthetized rat.

The possible importance of opioid peptides in the induction of long-term potentiation (LTP) was investigated in the perforant path-granule cell system. A high-frequency train (400 Hz) was delivered to the lateral or medial perforant path, during push-pull perfusion of the dentate molecular layer with artificial cerebrospinal fluid (CSF) alone, or with CSF containing naloxone (10(-4) M). Naloxone effectively blocked the induction, but not the maintenance of LTP in the lateral perforant path, a putative proenkephalin system. Naloxone did not affect the production of LTP in the medial pathway. These findings suggest that activation of naloxone-sensitive receptors is necessary for the full expression of LTP in the lateral perforant pathway.

Animals↗
PubMed1988

Increased hydrolysis of phosphatidylinositol-4,5-bisphosphate in long-term potentiation.

Inositol phospholipid hydrolysis was examined in slices and synaptosomes prepared from area CA3 of control hippocampi and hippocampi in which long-term potentiation (LTP) was induced in vivo. In both synaptosomes and slices, LTP was associated with an increase in [3H]inositol labelling of inositol phosphates but not phosphoinositides. Glutamate (10(-3) M) significantly increased labelling of inositol phosphates in slices obtained from control tissue but had no effect either in slices obtained from potentiated tissue or in synaptosomes obtained from control or potentiated tissue. The finding that glutamate had no significant effect in slices prepared from potentiated tissue suggests that glutamate-mediated stimulation of inositol phospholipid hydrolysis in a postsynaptic compartment may be saturated in LTP. The possibility that the increase in phospholipid hydrolysis associated with LTP which we report here may be linked with the previously reported increase in transmitter release is discussed.

Animals↗
PubMed1987

Increase in K+-stimulated, Ca2+-dependent release of [3H]glutamate from rat dentate gyrus three days after induction of long-term potentiation.

Long-term potentiation (LTP) was induced by unilateral tetanic stimulation of the perforant path in the dentate gyrus of rats with implanted electrodes. Evoked potentials were monitored for the subsequent 3 days in one group, and for 23 days in another. The dentate gyrus was removed bilaterally and slices prepared and stored in 10% DMSO/Krebs for subsequent analysis of K+-stimulated, Ca2+-dependent release of [3H]glutamate. In the 3-day group, in which the mean increase in the population EPSP was 35% at the time of sacrifice, release from the tetanized side was significantly greater than from the unstimulated side. In the 23-day group, both the increase in the EPSP and the increase in release from the tetanized side had declined to statistically insignificant levels. These results extend to a period of several days the previously observed association between LTP and increased K+-stimulated, Ca2+-dependent release of transmitter.

Animals↗
PubMed1987

Increase in [3H]glutamate release from slices of dentate gyrus and hippocampus following classical conditioning in the rat.

The release of amino acids was examined in three hippocampal areas following classical conditioning. Paired or unpaired tone(CS)-shock(US) presentations were given to animals engaged in a previously acquired food-motivated lever-pressing task. Conditioned suppression of lever-pressing was the behavioural measure of conditioning. The dentate gyrus and areas CA1 and CA3 of the hippocampus were removed bilaterally from conditioned and pseudoconditioned animals, and slices cut and stored in liquid nitrogen for subsequent in vitro analysis of the release of radiolabelled glutamate and aspartate. K+-stimulated release of radiolabelled amino acids was analysed in the presence and absence of extracellular Ca2+. Potassium-stimulated, Ca2+-dependent release of [3H]glutamate was significantly greater in slices of dentate gyrus and area CA1 prepared from conditioned animals than from pseudoconditioned animals. This finding identifies a neurochemical change associated with classical conditioning which is similar to the increase in transmitter release seen in hippocampal long-term potentiation (LTP), and which is consistent with the hypothesis that an LTP-like mechanism is involved in mnemonic processes.

Animals↗
PubMed1987

Long-term potentiation in the dentate gyrus: induction and increased glutamate release are blocked by D(-)aminophosphonovalerate.

D(-)Aminophosphonovalerate, a specific antagonist of the N-methyl-D-aspartate subtype of glutamate receptor, was perfused through a push-pull cannula into the dentate gyrus of rats anaesthetized with urethan in order to observe its effect on the induction and maintenance of long-term potentiation and on the increase in release of endogenous glutamate associated with long-term potentiation. The amplitude of the population spike evoked by single test shocks to the perforant path was significantly depressed by 100 microM D(-)aminophosphonovalerate, but there was a minimal effect on the slope of the population excitatory postsynaptic potential, or on the concentration of glutamate released into the perfusate. A brief high-intensity tetanus given to the perforant path while D(-)aminophosphono-valerate was being perfused failed to induce long-term potentiation or the sustained increase in glutamate release associated with long-term potentiation. Short-term post-tetanic potentiation was not affected. After wash-out of D(-)aminophosphonovalerate, a second high-frequency train produced both long-term potentiation and an increase in glutamate release which was sustained for the subsequent 1 h period of observation. D(-)Aminophosphonovalerate did not suppress long-term potentiation once it had been induced. D(-)Aminophosphonovalerate (100 microM) did not itself affect in vivo release of glutamate. However, in a separate series of in vitro experiments, D(-)aminophosphonovalerate at concentrations of 50 microM and above was found to depress the Ca2+ -dependent, K+-stimulated release of preloaded [14C]-glutamate from dentate slices.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1986

Correlation between long-term potentiation and release of endogenous amino acids from dentate gyrus of anaesthetized rats.

The relationship between long-term potentiation (l.t.p.) and the release of endogenous amino acid transmitters has been investigated in the dentate gyrus of rats anaesthetized with urethane. The molecular layer was perfused with artificial cerebrospinal fluid using a push-pull cannula. The perfusate was collected and analysed for glutamate, aspartate, glycine, glutamine and gamma-aminobutyric acid (GABA) using high-performance liquid chromatography (h.p.l.c.) with fluorometric detection. Recording electrodes were attached to the cannula to enable responses evoked by test stimuli to the perforant path to be monitored in the molecular and cell body layers. Perfusion was continued for 3 h while test stimuli were delivered to the perforant path at 30 s intervals. In the control group (n = 8), no further stimulation was given. In a second group (n = 8), a single high-frequency train (250 Hz for 200 ms) was delivered at the end of the first hour to induce l.t.p. The average potentiation of the slope of the excitatory post-synaptic potential (e.p.s.p.) 2 h later was 15%. In a third group (n = 8), the train to the perforant path was paired with a train to the commissural input to the dentate gyrus, a procedure which blocks the induction of l.t.p. In the potentiated group, there was an increase in the concentrations of glutamate and aspartate following the induction of l.t.p., relative to the decline seen in corresponding periods of the control group. This increase remained statistically significant for 1.5 h in the case of glutamate and for 45 min in the case of aspartate. There were no l.t.p.-associated changes in the release of glutamine or glycine; there was an indication that l.t.p. may be associated with a decrease in the release of GABA. Increasing the frequency and intensity of perforant path activation resulted in enhanced concentrations of glutamate and aspartate in the perfusate; no such changes occurred when granule cells were activated antidromically. We discuss the origin of the relative increases in the concentration of glutamate and aspartate which are found in the perfusate following the induction of l.t.p. and conclude that the most likely source is a sustained increase in activity-dependent release of these amino acids from perforant path terminals.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1985

Long-term potentiation of synaptic transmission in the dentate gyrus: increased release of [14C]glutamate without increase in receptor binding.

High-affinity uptake, K+-induced release and Cl -dependent binding of radiolabelled glutamate were examined in vitro in tissue prepared from the dentate gyrus of rats in which long-term potentiation (LTP) had been induced in vivo by a brief train of high-frequency stimulation. Release of preloaded L-[14C]glutamate was significantly greater in slices prepared from potentiated tissue than from control tissue. Uptake and binding were not significantly different. Release and uptake of L-[3H]aspartate were also studied in the same tissue: no significant difference was seen between the two groups. These results provide further evidence for an association between LTP and increased glutamate release but are inconsistent with previous reports that LTP is accompanied by an increase in glutamate binding.

Animals↗
PubMed1984

Structure and function of aberrant perforant path synapses in the hippocampus of neonatally X-irradiated rats.

We have examined the functional and morphological characteristics of synapses made by perforant path fibres projecting from the entorhinal cortex to the medial zone of the dentate area in adult rats which had been X-irradiated at birth, a procedure which prevents the proliferation of granule cells in that zone. We provide ultrastructural evidence that perforant path fibres in this region make synaptic contact with dendritic spines, and demonstrate that these synapses generate functional responses when the perforant path is stimulated. The evidence suggests that aberrant functional connections are made with the elongated basal dendrites of pyramidal cells.

Animals↗
PubMed1984

Hippocampal transplants in normal and reeler mice.

Hippocampal tissue taken from neonatal mice born of parents heterozygous for the reeler gene was transplanted into the brains of littermates. The great majority of transplants were from normal donors to normal hosts. A single case each of a reeler transplant into a normal host and a normal transplant into a reeler host is described. Reeler hippocampus transplanted into normal tissue retained the phenotype of reeler; normal hippocampus transplanted into reeler hippocampus was phenotypically normal.

Animals↗
PubMed1979

Projections to the ventral surface of the cat brainstem demonstrated by horseradish peroxidase.

Topical application of horseradish peroxidase (HRP) to the ventral surface of the medulla oblongata revealed various cells with axons terminating near this region. Fibers traced from the ventral surface originated in the nucleus of the tractus solitarius and the dorsal nucleus of the vagus, both near the dorsal surface of the medulla. Projections from the cochlear nucleus were also observed. Using short HRP contact time, fibers were shown which terminate at, or near, the ventral surface. The possible involvement of these projections in various responses mediated from the ventral surface is discussed.

Animals↗
PubMed1974

On the role of vasopressin and angiotensin in the development of irreversible haemorrhagic shock.

1. Long-lasting haemorrhagic hypotension (4.5 hr at 35 mmHg) leading to irreversible haemorrhagic shock, has been studied in normal dogs, in dogs treated with a bradykinin potentiating nonapeptide (BPP(9a)), which blocks the conversion of angiotensin I to angiotensin II, and in dogs with experimental chronic diabetes insipidus (DI dogs). BPP(9a) was given by I.V. injection before the start of bleeding (BPP pre-treated group), 45 min after blood pressure had reached 35 mmHg (BPP early treated group) or 2 hr after blood pressure had reached 35 mmHg (BPP late-treated group). After retransfusion of blood all dogs were allowed to recover and observed for a further period of 3 days.2. Untreated control dogs developed haemorrhagic shock with tachycardia, low cardiac output, low total peripheral conductance and low stroke volume. All died within 24 hr of retransfusion, with pathological lesions typical of irreversible haemorrhagic shock.3. BPP pre-treated dogs developed haemorrhagic shock with bradycardia (during early shock), high cardiac output, high peripheral vascular conductance and high stroke volume when compared with the untreated controls. All pre-treated animals survived the 3 day observation period. They were then killed and on post-mortem showed no signs of irreversible haemorrhagic shock.4. BPP early-treated animals behaved like controls before BPP, but like pre-treated animals after the drug. Only one out of eight died within the 3 day observation period.5. BPP late-treated dogs behaved like controls before BPP. They responded to the drug with a rise in cardiac output, peripheral vascular conductance and stroke volume, and with a fall in heart rate. These responses were, however, short-lived. Four out of these eight animals died within the 3 day observation period, with lesions of irreversible haemorrhagic shock.6. DI dogs developed haemorrhagic shock with tachycardia (like controls), but with high cardiac output and peripheral vascular conductance (like BPP pre-treated dogs). The stroke volume of DI dogs was intermediate between those of controls and pre-treated groups. All six dogs survived the 3 day observation period.7. BPP(9a) had no measurable effect on the course of endotoxic shock.8. It is suggested that the normally severe vasoconstriction of the mesenteric vascular bed, which is thought to be responsible for irreversible haemorrhagic shock, is absent or attenuated in the absence of vasopressin or angiotensin. The consequences of this on the development of irreversibility are discussed.

Angiotensin II↗