Biomedical subjects

S R Kelso

Publications and source records attributed to S R Kelso.

6 recordsLinked to original sources

PubMed1992

Protein kinase C-mediated enhancement of NMDA currents by metabotropic glutamate receptors in Xenopus oocytes.

1. N-Methyl-D-aspartate (NMDA) receptors were expressed in Xenopus oocytes injected with rat brain RNA. The modulation of NMDA-induced currents was examined by activating protein kinase C (PKC) either directly (using phorbol esters) or indirectly (via metabotropic glutamate agonists). 2. Bath application of the PKC activator, 4-beta-phorbol-12,13-dibutyrate (PDBu) resulted in a two-fold increase in the NMDA-evoked current at all holding potentials examined (-80 to 0 mV). The inactive (alpha) stereoisomer of phorbol ester was ineffective. 3. The increase was observed under conditions that eliminate the oocyte's endogenous calcium-dependent chloride current, which often contributes to the NMDA response in oocytes. 4. The PDBu effect was specific to the NMDA subclass of glutamate receptors in that no increase was observed in the responses to two other glutamate agonists, kainate and AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid). 5. Stimulation of PKC by activation of metabotropic receptors via either quisqualate or trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) also led to an increase in NMDA currents. 6. Both methods of enhancement induced transient effects. PDBu effects lasted 10-45 min, depending upon both dose and length of application. Quisqualate and trans-ACPD effects were shorter, lasting less than 10 min under these conditions of application. 7. Both methods of enhancement were blocked by the PKC inhibitor, staurosporine. In addition, the phorbol ester-induced enhancement of NMDA responses occluded further enhancement by quisqualate. 8. The results suggest a role for metabotropic glutamate receptors in modulation of NMDA-mediated processes.

Animals↗

PubMed1991

Trans-ACPD reduces multiple components of synaptic transmission in the rat hippocampus.

Activation of metabotropic quisqualate receptors by trans-ACPD (trans-1-aminocyclopentane-1,3-dicarboxylic acid) caused a reduction in the amplitude of the synaptic response elicited by stimulation of the Schaffer collateral projection and recorded intracellularly from area CA1 in slices of rat hippocampus. Pharmacological agents were used to isolate components of the response mediated by N-methyl-D-aspartate (NMDA) receptors, non-NMDA receptors, and gamma-aminobutyric acid (GABA) receptors. Each of these components was reduced during the trans-ACPD application. These results indicate that one subtype of glutamate receptor may be able to decrease the synaptic efficacy of other subtypes and may provide an important means for balancing the synaptic enhancement processes often studied in the hippocampus.

2-Amino-5-phosphonovalerate↗

PubMed1991

Activity-induced decrease in early and late inhibitory synaptic conductances in hippocampus.

The use dependence of inhibitory postsynaptic potentials (IPSPs) and their underlying conductances was studied in area CA1 of the hippocampal brain slice preparation, using a two-pulse paradigm in which paired activation of two separate synaptic inputs resulted in changes in the second, or "primed" response. In intracellular current-clamp recordings, the "primed" response, normally triphasic, exhibited a larger, wider excitatory PSP (EPSP) component and greatly reduced or absent IPSP components. Maximal widening occurred when the interval between synaptic stimuli was between 200 and 250 msec. Hyperpolarization of the postsynaptic cell reversed both the early IPSP and the direction of change of the width of the "primed" EPSP response, suggesting that the changes in the "primed" waveform were not due to the addition of an unidentified inward current(s). Furthermore, the reduction of the IPSPs during the "primed" response could not be accounted for by the fact that the membrane potential of the postsynaptic cell was hyperpolarized and therefore closer to IPSP reversal potential. Using single-electrode voltage-clamp techniques, we found that the early inhibitory conductance generally decreased by approximately 50%, with little if any change in reversal potential. The late inhibitory conductance also showed a priming-induced decrease of approximately 95%. Finally, "primed" four-pulse bursts of stimuli induced a larger depolarization in the postsynaptic cell than did unprimed bursts, also with an optimal interval of about 250 msec. We conclude that activation of certain synaptic pathways in the hippocampus results in a temporal window of 200-300 msec during which inhibitory synaptic activity is depressed and excitatory synaptic transmission is maximally effective, especially if the excitation occurs in short bursts. Such a mechanism would endow the inhibitory synaptic components of the hippocampus with a "gating" function to control long-term synaptic modification at excitatory synapses in the same region.

Animals↗

PubMed1991

Intracellular analysis of inherent and synaptic activity in hypothalamic thermosensitive neurones in the rat.

1. Intracellular neuronal activity was recorded in rat preoptic-anterior hypothalamic tissue slices. Thirty neurones were classified as warm sensitive, cold sensitive or temperature insensitive, based on their firing rate response to temperature changes. Seventy-seven per cent of the neurones were temperature insensitive, which included both spontaneously firing and silent neurones. Of all neurones, 10% were warm sensitive and 13% were cold sensitive. 2. Silent temperature-insensitive neurones had lower input resistances (126 +/- 21 M omega) than thermosensitive neurones (179 +/- 24 M omega). Regardless of neuronal type, however, resistance was inversely related to temperature. 3. Warm-sensitive neurones were characterized by a slow, depolarizing pre-potential, whose rate of rise was temperature dependent. This depolarizing potential disappeared during current-induced hyperpolarization, suggesting that intrinsic mechanisms are responsible for neuronal warm sensitivity. 4. Spike activity in cold-sensitive neurones correlated with putative excitatory and inhibitory postsynaptic potentials, whose frequency was thermosensitive. This suggests that cold sensitivity in these neurones depends on synaptic input from nearby neurones. 5. Like cold-sensitive neurones, action potentials of temperature-insensitive neurones often were preceded by short duration (less than 20 ms), rapidly rising pre-potentials, whose rates of rise were not affected by temperature. In some temperature-insensitive neurones, depolarizing current injection increased both firing rate (by 5-8 impulses s-1) and warm sensitivity, with pre-potentials having temperature-dependent rates of rise. We suggest that temperature-insensitive neurones employ two opposing, thermally dependent mechanisms: a voltage-dependent depolarizing conductance and a hyperpolarizing sodium-potassium pump.

Action Potentials↗

PubMed1990

Apparent desensitization of NMDA responses in Xenopus oocytes involves calcium-dependent chloride current.

N-Methyl-D-aspartate (NMDA) receptors were expressed and studied in Xenopus oocytes injected with rat brain RNA. NMDA application elicits a rapid inward current that decays in several seconds to a relatively stable level. This decay is reportedly due to desensitization. However, we found the early transient component could be evoked more than once during a single application of NMDA, suggesting that the receptor did not actually desensitize. Removal of external Ca2+, replacement of Ca2+ with Ba2+, or intracellular injection of EGTA abolished the transient component. Furthermore, a variety of Cl- channel blockers nearly eliminated the transient component and inhibited the plateau current as well. We propose that a significant portion of the NMDA current recorded in oocytes is carried by a transient inward Cl- current triggered by Ca2+ influx through the NMDA receptor/channel.

Animals↗

PubMed1989

Activity-induced depression of synaptic inhibition during LTP-inducing patterned stimulation.

In the hippocampus, patterns of electrical stimulation that approximate bursting neuronal activity during theta rhythm have been shown to induce a long-term potentiation (LTP) of excitatory synapses. In this study, a single subthreshold stimulus applied to one set of Schaffer/commissural fibers affected the response to a second stimulation delivered 200 ms later to a separate set of Schaffer/commissural fibers in the CA1 field of rat hippocampal slices. The first (priming) stimulus caused a prolongation of the synaptic response elicited by the second (primed) stimulus. In addition, the priming stimulation facilitated the induction of LTP by bursts of stimulation (4 pulses at 100 Hz) of the second afferent pathway. Analysis of the shape of the synaptic responses indicates that the prolongation is due to the removal of an inhibitory component rather than the addition of a novel excitatory component. Blockade of GABAA-ergic transmission with picrotoxin mimicked the priming effect in that it also widened synaptic responses and facilitated burst-induced LTP. We suggest that these patterns of stimulation result in a transient loss of inhibition during the primed stimulation. This, in turn, brings about a prolongation of the synaptic response that allows short bursts of excitatory synaptic activity to depolarize postsynaptic cells sufficiently to trigger LTP.

Animals↗