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C F Stevens

Publications and source records attributed to C F Stevens.

At least 109 records · Page 6Linked to original sources
PubMed1990

Failure to reverse long-term potentiation by coupling sustained presynaptic activity and N-methyl-D-aspartate receptor blockade.

The proposal that long-term potentiation (LTP) is a mechanism underlying memory in the mammalian brain rests on a number of properties of LTP that parallel characteristics of memory defined by behavior. A prominent feature of behaviorally defined memory is its reversibility. LTP is induced at synapses that correlate in their activity, and the signal for induction is calcium influx through N-methyl-D-aspartate (NMDA) receptor channels. By analogy to the reversibility of behaviorially defined memory, uncorrelated synaptic activity might be expected to reverse LTP, an anti-Hebbian effect called long-term depression, which has only recently been described in the hippocampus [Stanton, P. K. & Sejnowski, T. J. (1989) Nature (London) 339, 215-218]. Because the extent to which synaptic activity is correlated is represented by postsynaptic calcium concentrations, it seemed likely to us that long-term depression is related to the failure of calcium to pass through the NMDA channel. One way to block the calcium influx that signals correlated synaptic activity is with the NMDA receptor antagonist D-(-)-2-amino-5-phosphonovalerate. We performed a series of experiments in rat hippocampal slices designed to estimate the amount of synaptic depression per afferent test pulse under these conditions. Schaffer collateral-commissural afferents to field CA1 were repetitively stimulated in the presence of 2-amino-5-phosphonovalerate. No enduring synaptic depression nor reversal of LTP could be detected. We conclude that some other mechanism underlies long-term depression in the hippocampus.

2-Amino-5-phosphonovalerate↗
PubMed1990

Computational implications of NMDA receptor channels.

We have summarized the quantitative relations developed so far for the description of NMDA receptor function. One of the most important gaps in our knowledge relates to desensitization. A full quantitative treatment of computational uses of NMDA receptor channels must await a formalization of this process and also a more detailed examination of the occupation of closed states of the receptor whose binding sites are occupied. As this information becomes available and the role of NMDA receptors in the function of brain circuits is further explored, we should be able to define accurately this second computational mode.

Animals↗
PubMed1990

A quantitative description of NMDA receptor-channel kinetic behavior.

Currents evoked in neurons of the vertebrate CNS by the glutamate agonist N-methyl-D-aspartate (NMDA) exhibit a marked voltage dependence in the presence of extracellular Mg. At the single-channel level, the addition of external Mg alters single-channel openings from long-lived events to many very short events grouped into bursts of openings. These bursts apparently result from short interruptions of current flow during periods when the channel is in the open configuration. Single-channel currents evoked by NMDA have been studied in outside-out patches of membrane taken from hippocampal CA 1 neurons grown in dissociated cell culture. The effects of changing external Mg concentration and holding potential on the single-channel parameters of open time, closed time, and burst length have been successfully described assuming a 3- or 4-state model with 1 open state, 1 or 2 "blocked" states, and 1 absorbing closed state. Evaluation of the blocking rates over Mg concentrations from 0.2-200 microM indicate that a single "blocking" mechanism cannot account for the short closed states and that a second voltage-dependent but Mg-independent "blocked" state is necessary to explain the data especially at low Mg concentrations.

Animals↗
PubMed1990

Voltage dependence of NMDA-activated macroscopic conductances predicted by single-channel kinetics.

The conductance activated in many mammalian CNS neurons by the glutamate analog NMDA is inhibited at hyperpolarized potentials by extracellular magnesium. Whole-cell recordings from hippocampal neurons in culture were used to determine the voltage dependence of the NMDA conductance in the presence of extracellular magnesium concentrations from 1 microM to 10 mM. The conductance-voltage data are well fitted by a gating function derived from rate constants determined in an earlier study of the kinetic behavior of single channels activated by NMDA. The results are consistent with the assumption that magnesium inhibits current through the NMDA-activated channel by directly blocking the ion pore. In addition, another voltage-dependent blocking or flicker-producing mechanism has to be invoked to account for the behavior of the conductance at both the single-channel and whole-cell level, especially at low concentrations of extracellular magnesium.

Animals↗
PubMed1989

NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus.

A CENTRAL assumption about long-term potentiation in the hippocampus is that the two classes of glutamate-receptor ion channel, the N-methyl-D-aspartate (NMDA) and the kainate/quisqualate (non-NMDA) subtypes, are co-localized at individual excitatory synapses. This assumption is important because of the perceived interplay between NMDA and non-NMDA receptors in the induction and expression of long-term potentiation: the NMDA class, by virtue of its voltage-dependent channel block by magnesium and calcium permeability, provides the trigger for the induction of long-term potentiation, whereas the actual enhancement of synaptic efficacy is thought to be provided by the non-NMDA class. If both receptor subtypes are present at the one synapse, such cross-modulation could occur rapidly and locally through diffusible factors. By measuring miniature synaptic currents in cultured hippocampal neurons we show that the majority (approximately 70%) of the excitatory synapses on a postsynaptic cell possess both kinds of receptor, although to different extents. Of the remaining excitatory synapses, approximately 20% contain only the non-NMDA subtype and the rest possess only NMDA receptors. This finding provides direct evidence for co-localization of glutamate-receptor subtypes at individual synapses, and also points to the possibility that long-term potentiation might be differentially expressed at each synapse according to the mix of receptor subtypes at that synapse.

Action Potentials↗
PubMed1989

Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties.

Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[3H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These diarylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. Our results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack.

Animals↗
PubMed1988

Applications of quantitative measurements for assessing glutamate neurotoxicity.

The role of the N-methyl-D-aspartate receptor channel in glutamate neurotoxicity was investigated in cultured hippocampal neurons of the CA1 region. An equation, the survival function, was developed to quantify the effects of putative modulators of neurotoxicity. 2-Amino-5-phosphonovaleric acid (30 microM) reduced the neuronal sensitivity to glutamate by a factor greater than 20, whereas glycine (1 microM) enhanced it by a factor of 7.5 +/- 2.5. Neurons were protected by increasing Mg2+ concentrations in a predictable way based on the ion's ability to block the N-methyl-D-aspartate channel. These findings provide a quantitative basis for the assessment of various neuroprotective agents and add further support to the hypothesis that the N-methyl-D-aspartate channel is central to glutamate neurotoxicity.

2-Amino-5-phosphonovalerate↗
PubMed1987

Voltage-dependent gating of single sodium channels from mammalian neuroblastoma cells.

Single sodium channel currents have been studied in cell-attached patches from the mouse neuroblastoma cell line N1E115. Distributions of open duration, latency until first opening, and the average probability of a channel being open after a voltage step, p(t), were analyzed and compared to predicted distributions from various kinetic models for voltage-dependent gating. It was found that, over most of the voltage range under which channel gating occurs, the slow steps in gating are opening transitions and that inactivation of open channels is significantly faster than the decline in p(t) (tau h). This view of gating is confirmed by comparison of the kinetics of ensemble averages of single-channel currents obtained from step- and tail-current records at the same voltage. The probability of a channel reopening after having closed was calculated by comparing p(t) with the convolution of the first-latency probability density and the conditional probability of remaining open t milliseconds after opening. This reopening probability is small but slightly voltage dependent over the voltage range where the mean open duration remains constant and tau h changes considerably. The voltage dependence of open channel inactivation and deactivation were calculated from the probability of reopening and the mean open duration. The equivalent gating charge for the inactivation rate is a few tenths of an electronic charge, whereas the equivalent charge for the closing rate is 2.5-3.5 electronic charges.

Animals↗
PubMed1987

Sodium channel structure-function relations.

The arguments presented here cannot be made sufficiently precise to place clear limits on models of sodium channel function, but they do raise questions about the validity of simplest interpretations made so far. Thus, simple identification of a motion of each of the four S4 segments with a separate kinetic step in the sequence that leads to channel opening seems unlikely to be correct. As more detailed structural and functional information becomes available, attempts to relate structure and function in a quantitative way should indicate which features of the models are least in accord with data, and will help in deciding which among the various models that will arise is most satisfactory.

Amino Acid Sequence↗
PubMed1984

Biophysical studies of ion channels.

Ionic channels, the integral membrane proteins responsible for the brain's electrical activity, have long been studied with standard electrophysiological and biochemical methods. Recently, however, newly developed electrical and molecular biological methods have been brought to bear on long-standing questions in neurobiology. Goals of current channel research include elucidating the primary amino acid sequence and three-dimensional structure of channel species; the mechanisms of synthesis, sorting, membrane insertion, and degradation; and aspects of function such as gating, ion permeation and selectivity, and regulation. The latest research combines the new biochemical and electrophysiological techniques to reveal relations between molecular structure and function.

Animals↗
PubMed1983

Acetylcholine receptor channel ionic selectivity: ions experience an aqueous environment.

Alkali metal and alkaline earth cations pass readily through the acetylcholine receptor channel. Monovalent cations with larger crystal radii are more permeant than ones with smaller radii. For divalent ions, this selectivity sequence is reversed: smaller ions are more permeant than larger ones. This reversal in selectivity sequence with change of valence from 1 to 2 can be naturally accounted for by electrostatic interactions between the ion and its environment in the selectivity region of the channel. For monovalent ions, ion-dipole interactions dominate, and, for divalent ions, ion-induced dipole interactions are more important. The sign of these two types of effects is opposite and produces the reversal in the selectivity sequence. The magnitude of electrostatic interactions can be estimated from experimental data and suggests that the permeating ion's environment in the selectivity region of the channel is essentially like that in free water.

Animals↗