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P K Stanton

Publications and source records attributed to P K Stanton.

At least 37 records · Page 2Linked to original sources
PubMed1996

Distinct synaptic loci of Ca2+/calmodulin-dependent protein kinase II necessary for long-term potentiation and depression.

1. Extracellular bath application of the selective Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 to hippocampal slices in vitro blocked the induction of long-term depression (LTD) by low-frequency Schaffer collateral stimulation (1 Hz/15 min) of the same concentration as has been shown previously to prevent induction of long-term potentiation (LTP) at these synapses. 2. In contrast, postsynaptic intracellular infusion of KN-62 into single CA1 pyramidal neurons did not prevent induction of LTD, although it was quite effective in blocking LTP. 3. We conclude that there is a presynaptic CaMKII that must be activated to induce LTD, whereas postsynaptic CaMKII stimulation is needed to evoke LTP. 4. Bath application of KN-62 also blocked depotentiation by low-frequency stimuli of previously induced LTP, suggesting that induction of depotentiation and de novo LTD may require the same CaMKII-dependent mechanisms.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Transient protein kinase C activation primes long-term depression and suppresses long-term potentiation of synaptic transmission in hippocampus.

Activity-dependent long-lasting plasticity in hippocampus and neocortex includes long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength. Recent studies have confirmed theoretical predictions that the sensitivity of LTP- and LTD-inducing mechanisms is dynamically regulated by previous synaptic history. In particular, prior induction of either repeated short-term potentiations or LTP lowers the threshold for induction of LTD and raises the threshold for LTP. In the current study, transient activation of protein kinase C with phorbol 12,13-diacetate was able to substitute for synaptic activity in priming synapses to exhibit enhanced homosynaptic LTD and to suppress the induction of LTP at Schaffer collateral synapses in area CA1 of hippocampal slices. This priming lasted 30 min, but not 3 hr, following phorbol 12,13-diacetate bath application. These data suggest that a protein kinase C-sensitive phosphorylation site may be an activity-sensitive target mediating the rapid expression of LTP and LTD.

Animals↗
PubMed1995

Resistance of hippocampal synaptic transmission to hypoxia in carbonic anhydrase II-deficient mice.

Mutant Car2n/Car2n mice deficient in carbonic anhydrase II (CA II; a major brain CA isozyme) suffer from systemic acidosis and are more resistant to experimental seizures than their normal littermates (+/+ or +/Car2n). The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been shown to contribute to long-term potentiation (LTP) of synaptic transmission, hypoxic/ischemic neuronal injury and to be blocked by extracellular protons (acidosis). We compared the effects of hypoxia on synaptic transmission and LTP in field CA1 of hippocampal slices from CA II-deficient mice to their normal littermates. Slices were subjected to successive 5, 10 and 15 min-periods of hypoxia with 30 min-recovery periods in between. Hippocampal slices from mutant, CA II-deficient mice, were more resistant to all periods of hypoxia tested than slices from normal littermates. In a separate set of mutant and normal slices, there were no differences in LTP of population spike amplitude. The relative resistance of CA II-deficient mice to hypoxia-induced damage may be a consequence of severe interstitial acidosis. The sustained influence of increased extracellular proton concentrations may change the characteristics of NMDA receptors resulting in an increased resistance of synaptic transmission in CA II-deficient mice to hypoxia compared to controls.

Animals↗
PubMed1995

Phospholipase A2 activation is not required for long-term synaptic depression.

Low-frequency synaptic stimulation evokes long-term depression of synaptic strength. One hypothesis is that modification of AMPA receptors by phospholipase A2 causes long-term depression. A previous study reported bromophenacylbromide, a completely nonselective phospholipase A2 inhibitor, blocked long-term depression at Schaffer collateral-CA1 synapses in hippocampus. In contrast, I show here that 3-(4-octadecyl)-benzoylacrylic acid (OBAA), a much more potent and selective inhibitor of low and high molecular weight phospholipase A2, does not block long-term depression at these same synapses, indicating that phospholipase A2 is not necessary for modifications causing long-term depression.

Acrylates↗
PubMed1995

Long-term potentiation and depression of synaptic transmission in rat posterior cingulate cortex.

We used stimulation of corpus callosum (CAL) and the subiculo-cingulate tract (SCT), in an in vitro brain slice preparation, to study activity-dependent changes in synaptic efficacy in posterior cingulate cortex (PCC). SCT stimulation monosynaptically excites the apical dendrites of deep laminae (V-VI) pyramidal neurons, while CAL afferents drive these same cells via synapses on their basal dendrites. In contrast, most superficial laminae (II/III-IV) pyramids appear to be driven polysynaptically via ascending axonal collaterals of deep pyramids. In slices retaining these connectivities, we contrasted characteristics of synaptic plasticity in superficial vs deep laminae field and intracellular potentials evoked by conditioning stimuli given at frequencies of 100, 20, 8, 5 and 1 Hz. Tetanic stimulation (100 Hz) of SCT or CAL yielded homosynaptic long-term potentiation (LTP) of each pathway, while stimulus trains of 8-20 Hz did not. 1-5 Hz stimulation of SCT and CAL elicited homosynaptic long-term depression (LTD) of synaptic strength in each pathway. Associative LTD was induced by interleaving 5 Hz pulses to the SCT pathway with 100 Hz theta-burst stimulation of CAL, but was not induced when these stimulus loci were switched. Heterosynaptic non-associative LTD was also observed in the alternate pathway following tetanization of either SCT or CAL. In all cases, LTP and LTD were observed only in deep laminae recordings. In contrast, superficial records showed only paired-pulse facilitation and short-term post-tetanic potentiation. In in vivo experiments in anaesthetized rats, PCC responses to SCT stimulation were contrasted with responses to stimulation of anteroventral and anterodorsal thalamic nuclei (AV/AD). SCT-elicited field potentials closely resembled those evoked in the slice, with maximal amplitude tuned to the 4-8 Hz frequency band. AV/AD stimulation elicited field potentials which were not frequency tuned. Overall, these data suggest that the acute circuit properties of PCC superficial laminae, modulated by thalamic input and synaptic plasticity in deep laminae, can transform hippocampal synaptic inflow before relaying it to extracingulate targets.

Animals↗
PubMed1995

Long-term potentiation and N-methyl-D-aspartate receptors: foundations of memory and neurologic disease?

Understanding the physiology of learning and memory is one of the great challenges of neuroscience. The discovery in recent years of long-term potentiation (LTP) of synaptic transmission and the elaboration of the mechanisms involved, in particular the NMDA receptor, offers the prospect not only of improving our understanding of normal memory storage and retrieval, but may also yield insights about various neurological and psychiatric clinical disorders. In this review, we begin by examining the different forms, properties, and methods of inducing LTP, followed by a description of molecular mechanisms thought to underlie the phenomenon. Molecular structure of the receptor is discussed, along with the roles of Ca2+ second messenger systems, synaptic morphology changes, and retrograde messengers in LTP. Finally, implications of the NMDA receptor and LTP in learning, memory, and certain clinical conditions such as epilepsy, Alzheimer's disease, and schizophrenia are discussed.

Animals↗
PubMed1994

Phenytoin protects against hypoxia-induced death of cultured hippocampal neurons.

The neuroprotective actions of the anticonvulsant phenytoin (diphenylhydantoin, PHT) were evaluated using 3 week old primary hippocampal cultures derived from 19 day embryonic rat. When added to the culture medium prior to a hypoxic insult, PHT increased neuronal viability two-fold. Doubling extracellular Mg2+ concentration was similarly neuroprotective. In contrast, PHT was unable to protect against hypoxia-induced death in one week old cultures, nor was PHT protective against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in cultures of either age. These findings suggest that non-NMDA receptor mechanisms are important in hypoxia-induced neuronal death, and may have important implications for the treatment of stroke.

Animals↗
PubMed1994

Lowering of extracellular pH suppresses low-Mg(2+)-induces seizures in combined entorhinal cortex-hippocampal slices.

Lowering [Mg2+]o induces epileptiform bursting in hippocampus and entorhinal cortex (EC), presumably by activation of N-methyl-D-aspartate (NMDA) receptors. Since increasing [H+]o has been shown to reduce NMDA receptor activation, we hypothesized that this could contribute to anticonvulsant actions of acidic pH. To test this, we studied the effects of raising extracellular PCO2 (20.6%, pH = 6.7) or lowering extracellular pH (6.7 or 6.2) on low-Mg(2+)-induced epileptiform discharges. Lowering the pH to 6.7 by either means increased the interval between seizure-like events (SLEs), decreased the maximal amplitude of SLEs, and if the site of seizure generation was at a distance from the recording site, acidification slowed the rate of seizure propagation. In contrast, the duration of SLEs was unaffected by acidic pH or high PCO2. Raising PCO2 or lowering pH to 6.7 also blocked early (8-10 min) but not late (> 20 min) phases of status-like discharges. All effects of the extracellular pH changes were fully reversible. Further lowering of extracellular pH to 6.2 completely and reversibly blocked both SLEs and status-like discharges. Our data show that the effects of high PCO2 and low pH on seizures in the EC in vitro may be dose-dependent and consistent with induction by proton blockade of NMDA receptors. Thus, blockade of NMDA currents by protons may be an important component of the anticonvulsant action of extracellular acidosis. The results also suggest that acidosis may be a desirable property for new antiepileptic treatments.

Acidosis↗
PubMed1993

Microcircuitry of posterior cingulate cortex in vitro: electrophysiology and laminar analysis using the current source density method.

We used current source density (CSD) analysis of a laminar profile of subicular stimulus-evoked field potentials recorded in cortical slices in vitro to characterize the interlaminar microcircuitry of posterior cingulate cortex. Neuroanatomic and electrophysiologic data indicate that subiculocingulate tract (SCT) afferents monosynaptically excite apical dendrites of deep laminae (V-VI) neurons, evoking pure EPSPs, while superficial laminae (II/III-IV) neurons are driven polysynaptically, evoking a mixture of longer latency EPSPs and IPSPs. Consistent with this model, CSD analysis of field potential laminar profiles supports the conclusion that activation of excitatory subicular afferent terminal fields in superficial laminae of cingulate cortex elicits primary monosynaptic activation of apical dendrites of deep lamina (V-VI) pyramids. Subsequent EPSP propagation to the somata of these pyramids generated synchronous action potential discharges which appeared to elicit delayed polysynaptic activation of superficial laminae pyramids and interneurons. Latency differences between SCT-stimulus-evoked EPSPs and action potentials in superficial and deep laminae were minimized by stimulus train frequencies of 5-8 Hz, indicating that the proposed microcircuitry can show functional tuning at frequencies characteristic of hippocampal neuronal activity (theta). Such tuning suggests that hippocampal output activity frequency and phase locked to theta rhythm will be preferentially gated through cingulate cortex.

Afferent Pathways↗
PubMed1993

31P-NMR study of transient ischemia in rat hippocampal slices in vitro.

Intracellular high energy phosphates (HEP) were monitored in rat hippocampal slices in vitro by 31P-NMR during continuous superfusion, no flow and reperfusion in order to model the changes which occur during cerebral ischemia and reperfusion in vivo. With continuous superfusion, stable intracellular HEP resonance signals were observed for over 4 h. When superfusion was stopped, there were rapid decreases in pH and phosphocreatine levels followed by slower loss of ATP. These changes are similar to those observed during cerebral ischemia in vivo by 31P-NMR. Upon reperfusion, the pH returned to normal, but the extent of HEP recovery depended on the length of time superfusion was halted. Following a 10 min ischemic period HEP levels returned to greater than 90% of preischemic values, while following a 16 min ischemic period there was only 60% recovery. Superfusion with low calcium, high magnesium medium significantly improved the recovery of HEP following 16 min of ischemia to 80% of preischemic levels. These data support the hypothesis that calcium influx during and following ischemia can disrupt energy metabolism in the hippocampus, and that magnesium can have a protective action on cellular energy status, perhaps by further blocking calcium influx.

Adenosine Triphosphate↗
PubMed1993

Age dependence of homosynaptic non-NMDA mediated long-term depression in field CA1 of rat hippocampal slices.

It has been hypothesized that high levels of presynaptic activity that fail to activate postsynaptic N-methyl-D-aspartate (NMDA) receptors may lead to long-term depression (LTD). Therefore, we tested the ability of high-frequency (50 Hz) synaptic stimulation in the presence of a blocker of NMDA receptors to elicit homosynaptic LTD at Schaffer collateral-CA1 synapses in hippocampal slices from 15-, 30- and 60-day-old rats. In control slices, there were no developmental differences in the incidence of long-term potentiation (LTP) of either EPSP slope or population spike amplitude. However, while NMDA receptor blockade with the specific antagonist D-2-amino-5-phosphonopentanoic acid (AP5; 25 microM) completely eliminated LTP in 30 and 60-day-olds, a significant number of slices from 15-day-old rats displayed some non-NMDA LTP of synaptic transmission. Moreover, under NMDA receptor blockade, the same high-frequency stimulation now induced homosynaptic LTD of population spike amplitude in a significant number of slices from 15- and 60-day-old rats (47% and 42%, respectively) but not in 30-day-olds (7%). LTD of population spike amplitude was most pronounced in 15-day-old slices (27 +/- 6% of baseline), whereas, in 60-day-old slices, LTD was 81 +/- 3% of baseline. LTD of EPSP slopes occurred in 44% of 15-day-olds, 13% of 30-day-olds, and 33% of slices from 60-day-old rats; the magnitude of EPSP was similar in 15 and 60-day-old slices (70 +/- 9% versus 81 +/- 1% of baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1993

Priming of homosynaptic long-term depression in hippocampus by previous synaptic activity.

Mechanisms regulating long-lasting, activity-dependent decreases in synaptic strength are poorly understood. Theoretical studies have suggested that the critical level (threshold) of synaptic activity needed to induce long-term depression (LTD) versus potentiation (LTP) of synaptic transmission should vary as a function of previous synaptic activity. In order to determine whether such a 'sliding threshold' is indeed a physiological phenomenon, we stimulated Schaffer collateral afferents in area CA1 of rat hippocampal slices at frequencies from 1 to 5 Hz before or after inducing LTP.

Animals↗
PubMed1992

Enhanced sensitivity of hippocampal pyramidal neurons from mdx mice to hypoxia-induced loss of synaptic transmission.

The gene at the Duchenne/Becker muscular dystrophy locus encodes dystrophin, a member of a protein superfamily that links the actin cytoskeleton to transmembrane plasmalemmal proteins. In mature skeletal myocytes, the absence of dystrophin is associated with decreased membrane stability, altered kinetics of several calcium channels, and increased intracellular calcium concentration. In the central nervous system, dystrophin is restricted to specific neuronal populations that show heightened susceptibility to excitotoxic damage and is localized in proximal dendrites and the neuronal somata. We report that CA1 pyramidal neurons in a hippocampal slice preparation from a dystrophin-deficient mouse genetic model of Duchenne muscular dystrophy (the mdx mouse) exhibit significant increased susceptibility to hypoxia-induced damage to synaptic transmission. This selective vulnerability was substantially ameliorated by pretreatment with diphenylhydantoin, an anticonvulsant that blocks both sodium-dependent action potentials and low-threshold transient calcium conductances. These findings suggest that dystrophin deficiency could predispose susceptible neuronal populations to cumulative hypoxic insults that may contribute to the development of cognitive deficits in Duchenne/Becker muscular dystrophy patients and that the effects of such periods of hypoxia may be pharmacologically remediable.

Animals↗
PubMed1992

Noradrenergic modulation of epileptiform bursting and synaptic plasticity in the dentate gyrus.

The neurotransmitter norepinephrine (NE) has been implicated in both the normal expression of long-term neuronal plasticity and in development of epileptiform bursting. Our studies have focused on the modulatory role of NE in a number of epilepsy models, both acute and chronic. Acutely, reduction of extracellular Mg2+ concentration in in vitro brain slices induced spontaneous and evoked epileptiform activity in both the entorhinal cortex (EC) and dentate gyrus (DG), due largely to removal of the voltage-dependent Mg2+ blockade of N-methyl-D-aspartate receptors. Spontaneous ictal events are most prominent in the EC, suggesting an importance of this area in seizure generation. NE was found to exhibit differential modulation of epileptiform activity in the EC and DG. In the EC, NE, acting via alpha 1-receptors, completely blocked low Mg(2+)-induced epileptiform activity. In contrast, in the DG, NE exhibited a beta-receptor mediated prolongation of the low Mg(2+)-induced ictal events, and enhanced the stimulus-induced ionic and field potential changes. These complementary modulatory actions in the EC and DG, may serve to enhance signal transmission through the DG, while simultaneously reducing EC input noise and exerting a potent antiepileptic action in the EC. Chronically, actions of NE in the DG were examined before and after kindling-induced epilepsy, neuronal plasticity produced by daily high-frequency stimulation. NE, acting on beta 1-receptors, depolarized granule cells, increased input resistance, firing and influx of Ca2+ in response to repetitive stimulation, and elicited long-lasting potentiation of synaptic potentials. In addition, NE acting via alpha 1-receptors, attenuated Ca(2+)-dependent regenerative potentials. After kindling-induced plasticity, there were marked reductions in all these effects of NE on granule cells, changes likely to influence kindling-induced seizures, protecting against further enhancement of excitability once plasticity is in place.

Afferent Pathways↗
PubMed1991

2-Amino-3-phosphonopropionic acid, an inhibitor of glutamate-stimulated phosphoinositide turnover, blocks induction of homosynaptic long-term depression, but not potentiation, in rat hippocampus.

Recently, we have reported an associative long-term depression (LTD) of synaptic strength in hippocampal field CA1 that is produced when a low-frequency test input is negatively correlated in time with a high-frequency conditioning input. We have also found that pairing of synaptic activity with postsynaptic hyperpolarization is sufficient to induce LTD. We report here that 2-amino-3-phosphonopropionate (AP3), a selective inhibitor of phosphoinositide (PI) turnover mediated by the metabotropic glutamate receptor, blocks the induction of associative LTD in hippocampal field CA1, but does not impair the induction of LTP. Our data suggest that metabotropic glutamate receptor activation is involved in the induction of LTD.

Alanine↗
PubMed1991

Resistance of the immature hippocampus to seizure-induced synaptic reorganization.

Temporal lobe epilepsy is a common form of epilepsy in human adults and is associated with a unique pattern of damage in the hippocampus. The damage includes cell loss of the CA3 and CA4 areas and synaptic growth (sprouting) of mossy fibers in the supragranular layer of the dentate gyrus. Experimental evidence indicates that in adult rats the excitatory amino acid, kainic acid, induces a similar pattern of changes in hippocampal circuitry associated with alterations in perforant path excitation and inhibition. It has been suggested that, in humans, this type of damage may be a result of seizures early in life. In this study we examined the effects of kainic acid-induced status epilepticus on synaptic reorganization and paired-pulse electrophysiology in developing rats and adults. Kainic acid induced more severe seizures in 15-day-old rat pups than in adults. In contrast to adult rats, these seizures did not produce CA3/CA4 neuronal loss, mossy fiber sprouting or changes in paired-pulse excitation or inhibition in the hippocampus of rat pups tested 2-4 weeks after status epilepticus. Our results provide evidence that the immature hippocampus may be more resistant to seizure-induced changes than the mature hippocampus.

Animals↗