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J V Halliwell

Publications and source records attributed to J V Halliwell.

At least 19 recordsLinked to original sources
PubMed2001

Electrophysiological characterization of laminar synaptic inputs to the olfactory tubercle of the rat studied in vitro: modulation of glutamatergic transmission by cholinergic agents is pathway-specific.

We have exploited the complementary arrangement of afferents in a coronal slice (300-400 microm) of the rat olfactory tubercle (OT) maintained in vitro to investigate transmission in two separate synaptic pathways. We recorded extracellular responses within the OT dense cell layer in slices and stimulated either the outermost layer to activate primary olfactory fibres or deeper to activate secondary input. Superficial stimulation produced a synaptic potential with superimposed population spike. This interpretation was based on blockade by calcium removal from the bathing medium and the use of the glutamate antagonist DNQX (10 microM); the spike was found to be selectively suppressed by tetrodotoxin applied near the cells. The spike, but not the synaptic wave, was depressed by 12 mM Ca2+ and enhanced by 1 mM Ba2+ in the bathing medium. Deep stimulation to activate association and intrinsic fibres elicited a nerve volley followed by a later response, also blocked by Ca2+ removal or 10 microM DNQX. It was unaffected by high Ca2+ or Ba2+, hence resulting from synaptic and not action current flow. Removal of Mg2+ from the bathing medium revealed an NMDA component of synaptic transmission at both loci that was selectively blocked by D-AP-5. The deep synaptic response, only, was depressed by carbachol IC50 7 microM or muscarine IC50 13 microM. This depression was also induced by AChE inhibitors eserine or tacrine and was antagonized by 1 microM atropine or 5-10 microM clozapine. These results characterize transmission in the OT and demonstrate a role for muscarinic modulation of deeper synapses in the OT that is influenced by psychotherapeutic drugs.

Animals↗
PubMed1998

Evidence for enhancement of gap junctional coupling between rat island of Calleja granule cells in vitro by the activation of dopamine D3 receptors.

1. Using patch-clamp techniques, we have studied actions of dopamine and related compounds on granule neurones within the islands of Calleja in vitro, in slices if approximately 200 microns thickness or as groups of varying cell number following enzymic digestion. 2. Prior to agonist application, island of Calleja granule cells displayed spontaneous stepwise shifts in whole-cell conductance ranging from 104 to 632 pS. The reversal potentials of these conductance changes ranged widely and matched the distribution of the cells' membrane potentials. Reversal potentials and membrane potentials shifted equally when cells were uniformly depolarized in 24 mM external K+. 3. Bath-applied dopamine elicited, after a delay of 4-9 min, an exaggerated form of the spontaneous behaviour that frequently gave way to a sudden large (up to thirtyfold) conductance change. At concentrations of 100-300 nM, a range of agonists with increasing affinity for the D3 receptor (apomorphine, quinpirole, 7-OH DPAT and PD 128907) triggered the response. The actions were neither mimicked by SKF-38393 nor antagonized by SCH-23390 (a selective D1 agonist and antagonist, respectively). Haloperidol reversibly blocked responses elicited by the D3/D2 agonist quinpirole. The action of effective agonists was maintained when transmitter release was abolished. Given the reported lack of D2 receptors in the islands of Calleja, these findings indicate a direct action of dopamine at the D3 receptor. 4. The dopaminergic effects were not affected by Gd3+ or substantial replacement of external Na+ with TEA, Tris or choline, eliminating stretch-activated channels but suggesting that if transmembrane channels were to be involved in this dopaminergic action they posseses a non-selective permeability to large cations. The reported presence of gap junctions in the islands of Calleja offers the explanation that these effects derive from enhanced activity of such channels or their hemi-constituents. 5. In testing the possible involvement of gap junctional coupling the following experimental observations were made: (i) alkalinization of slices mimicked the effect of D3 agonists; (ii) in cell groups, recording from pairs provided evidence of intercellular coupling, and mechanical separation of recorded neurones from neighbouring cells during the agonist-evoked response caused shutdown of the additional conductance; (iii) when applied to slices, the gap junctional blocker, 18 alpha-glycyrrhetinic acid, whilst not preventing the full-blown dopamine response, significantly reduced both the variance of recorded granule cell input conductance and the cells' apparent capacitance. 6. Taken together the results indicate a D3 action in granule cells, which is best explained by a dopaminergic promotion of intercellular coupling. The physiological relevance of such a mechanism is discussed.

Animals↗
PubMed1995

Membrane properties of the granule cells of the islands of Calleja of the rat studied in vitro.

1. Using patch-clamp techniques, we have studied granule neurones from the islands of Calleja in vitro: as isolated cells or as groups of varying numbers following enzymic digestion, or within untreated slices of approximately 100 microns thickness. 2. Recordings were made with patch pipettes in conventional or nystatin-perforated whole-cell mode. Current-clamp recordings indicated that these granule cells are excitable and at resting potential produce irregular spontaneous activity. In voltage clamp the transient inward current underlying these action potentials could be evoked. This current had a threshold for activation of about -50 mV and was sensitive to TTX. In some cells a TTX-resistant transient inward current was observed with a threshold for activation of about -70 mV. 3. Island of Calleja granule cells also exhibited outward currents. A rapidly activating transient current was observed that was resistant to TEA and sensitive to 4-AP, and therefore resembled IA. The current was half-maximally activated at -6 mV and steady-state inactivation was half-complete at -65 mV. 4. More sustained outward currents were also observed. Although some cells appeared to express a Ca(2+)-activated K+ current, the most common finding was a rapidly activating, slowly inactivating, voltage-dependent K+ current that was sensitive to TEA and Ba2+. This current resembled M-current more than delayed rectifier but displayed a number of idiosyncratic kinetic properties. Chief amongst these was the accumulation of an inactivating process when the current was repeatedly evoked from potentials near the cells' resting value by voltage steps that by themselves produced no observable inactivation during the voltage command; this behaviour was similar to the 'C-terminal' inactivation exhibited by lymphocytes and certain expressed K+ channel clones (Kv1.3). 5. These results indicate that the granule cells of the islands of Calleja are excitable and contain a number of additional regulatory conductances. The implications of these findings in, and the usefulness of this preparation to, the elucidation of the function(s) of the islands of Calleja are discussed.

Animals↗
PubMed1994

Barium ions fail to support neurotransmission at a central synapse.

Synaptic transmission in the CA1 area of the hippocampal slice preparation in vitro was studied in bathing media containing different levels of divalent cations. Transmission was abolished by replacing the normal levels (2.5 mM) of Ca2+ with 3 mM Mg. Transmission was not permanently restored by subsequent addition of Ba2+ but added Ca2+ was effective. Transient reappearance of synaptic currents were seen when Ba2+ was added at a time when contaminating levels of Ca2+ were still present, but neurotransmission waned as [Ca2+]e declined with protracted washout. In accordance with this interpretation, Ba2+ potentiated the transmission observed in the presence of low concentrations (0.25 mM) of Ca2+. Little evidence was found for Ba2+ effects at axonal sites but the potentiation of synaptic transmission by Ba2+ could be accounted for in terms of a blockade of terminal K-channels.

Action Potentials↗
PubMed1993

Carbachol potentiates Q current and activates a calcium-dependent non-specific conductance in rat hippocampus in vitro.

Intracellular recordings were made from CA1 neurons in rat hippocampal slices maintained in vitro. When Na+ currents were blocked with tetrodotoxin and K+ conductances known to be sensitive to suppression by muscarinic agonists were blocked by 2 mM Ba2+, CA1 cells were depolarized by carbachol (3-10 microM) with an attendant conductance increase, whereas prior to Ba2+ the agonist produced a decrease or no change in conductance. Under voltage clamp at approximately -60 mV and in the presence of tetrodotoxin and Ba2+, carbachol (3-10 microM) induced a variable-latency biphasic inward current of up to 380 pA associated with a conductance increase of approximately 50%. The first phase was associated with an increase (more than 2-fold) of the Cs(+)-sensitive, hyperpolarization-activated cationic current, IQ. Carbachol also accelerated the kinetics of IQ at -100 mV with an average 24% reduction in its activation time constant. The second phase reflected an additional inward current that was Cs(+)-resistant, displayed little apparent voltage sensitivity and had a mean extrapolated reversal potential, determined in the presence of external Cs+ (< or = 5 mM), of approximately -20 mV. In a small proportion of cells the second phase of inward current was followed (or overlapped) by an outward current, also associated with a conductance increase, which reversed at approximately -70 mV. These carbachol actions were prevented by extracellular 300 microM Cd2+ and 2 mM Mn2+, by high levels (> 5 mM) of extracellular Mg2+ or Ca2+, and by omission of Ca2+ or reduction of extracellular Na+ to 25 mM by substitution of NaCl with Tris or N-methyl-D-glucamine. Carbachol action was not mimicked by oxotremorine (< or = 60 microM), but was irreversibly blocked by this drug. Likewise, atropine (100 nM) irreversibly and gallamine (10 microM) reversibly antagonized carbachol's action. The action of carbachol was blocked shortly after prior exposure of slices to 2-5 mM caffeine. Chronic or acute incubation of slices with 2 mM Li+ potentiated (between 1- and 2-fold) carbachol responses. The data indicate that muscarinic activation increases cationic flux by a calcium-dependent potentiation of IQ and activation of a non-selective conductance. The probability that inositol phospholipid metabolism is involved in triggering these events is discussed.

Animals↗
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↗
PubMed1984

Somatically recorded Ca-currents in guinea-pig hippocampal and olfactory cortex neurones are resistant to adenosine action.

Inward membrane currents were recorded in tetrodotoxin-treated neurones of hippocampus and olfactory cortex in vitro after impalement with CsCl-containing microelectrodes to suppress potassium conductances. They were blocked by the Ca2+ -channel blocker Cd2+ but were unaffected by adenosine alone (up to 1 mM), adenosine (20 microM) in the presence of the uptake blocker dipyridamole (1 microM) or the stable analogue cyclohexyladenosine (100 microM). This ineffectiveness of adenosine on Ca-currents was in contrast to its known potent suppression of synaptic transmission in these preparations, and its inhibition of Ca-dependent action potentials.

Adenosine↗
PubMed1984

The action of cholinomimetic substances on impulse conduction in the habenulointerpeduncular pathway of the rat in vitro.

The effects of some cholinomimetic substances and their antagonists on the peak height of compound action potentials recorded from the terminal region of the habenulointerpeduncular pathway have been studied using a rat brain slice preparation. Carbachol and acetylcholine (ACh) depressed the peak height of the compound action potential and increased the latency to peak. The nicotinic agonists nicotine and dimethylphenylpiperazinium depressed the peak height of the compound action potential while muscarine and glutamate had no effect. The depressant effect of carbachol was blocked by the nicotinic antagonists hexamethonium, mecamylamine and d-tubocurarine but not by atropine. Physostigmine enhanced the effects of ACh and, to a lesser extent, carbachol. In the presence of physostigmine, carbachol or ACh initiated a spontaneous oscillation of the amplitude of the compound action potential which was Ca2+ dependent and was blocked by mecamylamine. It is concluded that depression of the amplitude of the compound action potential is due to activation of presynaptic nicotinic receptors. The results are discussed with reference to possible cholinergic mechanisms in the habenulointerpeduncular pathway.

Acetylcholine↗