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J V Halliwell

Publications and source records attributed to J V Halliwell.

17 recordsLinked to original sources
PubMed1990

A decrease in firing threshold observed after induction of the EPSP-spike (E-S) component of long-term potentiation in rat hippocampal slices.

Two components of long-term potentiation (LTP) are distinguished with extracellular recording electrodes: a synaptic and an EPSP-Spike (E-S) component. The latter consists of the enhancement produced in the population spike amplitude in excess of that predicted by EPSP potentiation alone. The experiments carried out in this study were designed to investigate intracellular correlates of E-S potentiation and to examine the hypothesis that an increased postsynaptic excitability underlies E-S potentiation. CA1 pyramidal neurons were synaptically activated from stratum radiatum. LTP, defined as a stable increase in the probability of firing to afferent stimulation, was found to be related to a decrease in the intracellular PSP peak amplitude and slope required to fire the cells at a probability of 0.5. These changes were accompanied by a decrease in threshold to direct activation. No significant changes in input resistance or resting potential were recorded. These excitability changes were only observed in cells displaying LTP; they were not related to the potentiation of the synaptic component (PSP amplitude). Our results support the hypothesis that different mechanisms underlie the two components of LTP, and that a reduction in threshold for neuronal discharge accompanies tetanus-induced E-S potentiation. It is suggested that an increase in the ratio of synaptically evoked excitation/inhibition and a reduction in tonic synaptic inhibition through GABAA channels contribute to E-S potentiation.

Action Potentials↗
PubMed1990

Membrane currents in hippocampal neurons.

This chapter reviews properties and functions of endogenous ionic currents in hippocampal neurones. Currents considered are: Na currents INa(fast) and INa(slow); Ca currents; K currents--delayed rectifier IK(DR), transient IK(A), 'delay' current IK(D) and M current IK(M); inward rectifiers IQ, IK(IR) and ICl(V); Ca-activated currents IK(Ca) (IC and IAHP), ICl(Ca) and Ication(Ca); Na-activated currents; and anoxia-induced currents.

Animals↗
PubMed1989

The EPSP-spike (E-S) component of long-term potentiation in the rat hippocampal slice is modulated by GABAergic but not cholinergic mechanisms.

Long-term potentiation of synaptic efficacy (LTP) can be shown to consist of two components: a synaptic and an excitatory postsynaptic potential (EPSP)-spike (E-S) component. The E-S component is expressed as a leftward shift in the curve relating population spike amplitude as a function of EPSP slope. The participation of cholinergic and GABAergic processes in E-S potentiation was studied in field CA1 of rat hippocampal slices. Atropine, a muscarinic antagonist, did not prevent tetanus-induced E-S potentiation. The cholinergic agonist carbachol and the GABAA antagonist picrotoxin produced a leftward shift in the E-S relation; picrotoxin, but not carbachol, prevented the expression of tetanus-induced E-S potentiation. These observations indicate that an increase in the ratio of evoked excitation to inhibition and/or a reduction in tonic inhibition mediated by the activation of GABAA receptors contribute to E-S potentiation produced by high-frequency stimulation.

Action Potentials↗
PubMed1989

9-Amino-1,2,3,4-tetrahydroacridine (THA) blocks agonist-induced potassium conductance in rat hippocampal neurones.

The actions of 9-amino-1,2,3,4-tetrahydroacridine (THA) were studied on rat CA1 pyramidal neurones under voltage-clamp in transverse slices of hippocampus maintained in vitro. As previously reported, THA reduced the resting conductance of cells; THA also suppressed inward rectification activated by hyperpolarization by up to 75% (The dose of THA which reduced the response by 50% (IC50) was 300 microM). More sensitive to the action of THA was the outward K+ current activated in CA1 neurones by 5-HT, adenosine and baclofen. This was completely blocked by THA (IC50 = 28 microM). The cooperativity of this latter action of THA with its well-known anticholinesterase activity is discussed in relation to the therapeutic effects of THA in treating Alzheimer's disease.

Adenosine↗
PubMed1989

Cholinergic responses in human neocortical neurones.

Neurones in deeper layers of slices of temporal or frontal human neocortex maintained in vitro were impaled with microelectrodes and responses to cholinergic agonists were studied under current and voltage clamp conditions. A range of membrane currents were identifiable: inactivating and persistent Na(+)-conductances, inactivating and persistent Ca2(+)-conductances, two types of inward currents activated by hyperpolarization (IQ and If.i.r.) and voltage and Ca2(+)-activated K(+)-conductances, which were distinguished on the grounds of their characteristic voltage or pharmacological specificity. The cholinergic agonists muscarine or carbachol were applied in the medium superfusing the slices. Two major effects were observed: consistently, the time and voltage-dependent noninactivating K(+)-conductance IM was suppressed and, when Ca2(+)-influx was permitted (in the absence of Ca2(+)-channel blockers), a Ca2(+)-activated K(+)-conductance was transiently or persistently potentiated. Consistent with a suppression of IM, muscarine excited human neocortical neurones only when applied during a period of membrane depolarization to a potential at which IM would be expected to exert a braking effect on excitability. Applied at a potential negative to the M-current activation range, muscarine had no excitatory or even an inhibitory effect on the cell. Collectively, these results demonstrate that in the human, IM can be a target for cholinergic regulation and, in addition, complex effects of ACh on other conductances could modulate cell firing patterns.

Acetylcholine↗
PubMed1986

M-current in human neocortical neurones.

Intracellular recordings were made in slices of human neocortex that had been surgically excised from patients in order to remove deep lying brain tumours. In more than half the neurones studied under voltage-clamp (n = 9), a non-inactivating K+-current was detected that was turned on at potentials positive to around -60 mV. This conductance persisted when Ca2+-flux into neurones was blocked with Cd2+ and it was suppressed by muscarine (20 microM). The slow kinetics and voltage sensitivity of this K+ conductance, together with its muscarinic suppression, identified it as the M-current (IM). In addition to IM, evidence for the existence of Ca2+ and Ca2+-activated conductances was obtained in human neurones. These results validate the extrapolation of animal-derived data and identify IM as a target for cholinergic modulation in the human.

Acetylcholine↗
PubMed1986

4-Aminopyridine and dendrotoxin induce repetitive firing in rat visceral sensory neurones by blocking a slowly inactivating outward current.

In a subpopulation of rat visceral afferent neurones we have identified a potassium (K) current which is novel to mammalian neurones. It activates rapidly at potentials positive to - 70 mV but shows only slow and incomplete inactivation and is inhibited by 1-30 microM 4-aminopyridine (4-AP) or 3-10 nM dendrotoxin (DTX). Inhibition of this slowly inactivating current suppresses spike adaptation and leads to pronounced repetitive firing. In contrast, other visceral afferent neurones possessing the normal transient A-current were insensitive to 4-AP at concentrations below 100 microM. We suggest that inhibition of the slowly inactivating current may contribute to the convulsant actions of 4-AP and DTX.

Action Potentials↗
PubMed1986

Central action of dendrotoxin: selective reduction of a transient K conductance in hippocampus and binding to localized acceptors.

Dendrotoxin, a small single-chain protein from the venom of Dendroaspis angusticeps, is highly toxic following intracerebroventricular injection into rats. Voltage-clamp analysis of CA1 neurons in hippocampal slices, treated with tetrodotoxin, revealed that nanomolar concentrations of dendrotoxin reduce selectively a transient, voltage-dependent K conductance. Epileptiform activity known to be induced by dendrotoxin can be attributed to such an action. Membrane currents not affected directly by the toxin include (i) Ca-activated K conductance; (ii) noninactivating voltage-dependent K conductance; (iii) inactivating and noninactivating Ca conductances; (iv) persistent inward (anomalous) rectifier current. Persistence of the effects of the toxin when Cd was included to suppress spontaneous transmitter release indicates a direct action on the neuronal membrane. Using biologically active, 125I-labeled dendrotoxin, protein acceptor sites of high affinity were detected on cerebrocortical synaptosomal membranes and sections of rat brain. In hippocampus, toxin binding was shown autoradiographically to reside in synapse-rich and white matter regions, with lower levels in cell body layers. This acceptor is implicated in the action of toxin because its affinities for dendrotoxin congeners are proportional to their central neurotoxicities and potencies in reducing the transient, voltage-dependent K conductance.

Animals↗
PubMed1972

Intracellular pH in rat isolated superior cervical ganglia in relation to nicotine-depolarization and nicotine-uptake.

1. The intracellular pH (pH(i)) of rat isolated superior cervical ganglia incubated in normal Krebs solution (pH(o)=7.37) was estimated to be 7.33 from the uptake of a weak acid, (14)C-5,5-dimethyloxazolidine-2,4-dione (DMO). Addition of 30 muM nicotine for 30 min reduced the DMO-estimated pH(i) by 0.15 units to 7.18. This effect was prevented by hexamethonium (2.5 mM) or by depolarizing the ganglion with K(+) (124 mM).2. (3)H-Nicotine (30 muM) was concentrated within the ganglia to an intracellular/extracellular concentration ratio (C(i)/C(o)) of 5.54 in normal Krebs solution and 4.61 in 2.5 mM hexamethonium. This would suggest an intracellular pH of 6.54 and 6.63 respectively. In ganglia previously depolarized by K(+) the corresponding values for C(i)/C(o) were 4.02 (minus hexamethonium, estimated pH(i) 6.95) and 4.17 (plus hexamethonium, estimated pH(i) 6.94).3. A multicompartment cell interior comprising an acid cytoplasm (pH approximately 6.6) and more alkaline nucleus and mitochondria is proposed to explain the difference between the values of pH(i) estimated from the uptake of DMO and nicotine. It is suggested that the fall in pH(i) during nicotine-depolarization results from metabolic stimulation following Na(+) entry.

Animals↗
PubMedDate not supplied

Differential modulation of three separate K-conductances in hippocampal CA1 neurons by serotonin.

The hippocampus receives a dense serotonin-containing innervation from the divisions of the raphe nucleus. Serotonin applied to hippocampal neurons to mimic the action of endogenous transmitter often produces complex and variable responses (see for example ref. 3). Using voltage-clamp methods and new ligands that are selective for subtypes of serotonin receptors, we have been able to clarify the mechanism of serotonin action on CA1 cells in rat hippocampal slices. We describe three distinct actions of serotonin (or 5-HT) on identified K-conductances in these cells. First, it activates a Ca-independent K-current which is responsible for neuronal hyperpolarization and is inhibitory. Second, it simultaneously suppresses the slow Ca-dependent K-conductance that is largely responsible for the accommodation of cell firing in CA1 neurons: this produces a paradoxical increase in neuronal discharge in response to a depolarizing input. Third, serotonin produces a more slowly developing and long-lasting suppression of an intrinsic voltage-dependent K-conductance, Im (ref. 9), leading to neuronal depolarization and excitation. The hyperpolarizing response is mediated by class 1A serotonin receptors, whereas the other responses are not. Modulation of these different conductances by endogenously released serotonin could therefore change the probability or the duration (or both) of neuronal firing in the mammalian brain in different ways to give inhibitory, excitatory or mixed effects.

Action Potentials↗