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H Bostock

Publications and source records attributed to H Bostock.

71 records · Page 4Linked to original sources
PubMed1983

Potassium channel distribution in spinal root axons of dystrophic mice.

We have used 4-aminopyridine (4AP), a potassium channel blocker, to assess the presence and distribution of potassium channels in the congenitally abnormally myelinated spinal root axons of dystrophic mice. 1 mM-4AP slightly depressed the amplitude but had no effect on the half-width of the monophasic action potential of normal A fibres, indicating the absence of a significant concentration of potassium channels at normal mouse nodes of Ranvier. By progressively increasing stimulus intensity it was possible to elicit three more or less discrete components of the compound action potential from dystrophic mouse spinal roots, presumably corresponding to myelinated fibres, large diameter bare axons and, in the case of dorsal roots, C fibres. The amplitude and duration of all three components were increased on exposure to 4AP, indicating the presence of potassium channels in all types of dystrophic mouse spinal root axons. Conduction in single fibres was studied using longitudinal current analysis. Both saltatory and continuous conduction were observed corresponding to the myelinated and bare portions of dystrophic mouse spinal root axons. Three types of 'nodal' membrane could be inferred from the membrane current recordings from myelinated dystrophic mouse axons: (1) pure sodium channel membrane, (2) membrane containing both sodium and potassium channels, and (3) membrane containing predominantly, if not exclusively, potassium channels. The large early outward currents at the latter two types of nodes suggested that these nodes were wider than normal. Recordings of continuous conduction indicated that potassium channels were also distributed irregularly along bare portions of the dystrophic mouse axons. These abnormalities of ion channel distribution are interpreted as reflecting failure of normal axon-Schwann cell communication in the dystrophic mouse spinal roots.

Action Potentials↗
PubMed1983

The spatial distribution of excitability and membrane current in normal and demyelinated mammalian nerve fibres.

Thresholds to electrical stimulation have been recorded, concurrently with the membrane currents of conducted impulses, at many positions along undissected single fibres in rat spinal roots. In normal myelinated fibres, distinct threshold minima invariably coincided with sites of inward current generation, and were therefore identified as nodes of Ranvier. Between nodes, the thresholds rose by an order of magnitude. At normal nodes, the charge thresholds were linearly related to stimulus duration, as predicted by computer simulations of a model myelinated fibre (Bostock, 1983). The strength-duration time constants averaged 64.9 +/- 8.3 microseconds (mean +/- S.D.) at 37 degrees C, and had a Q10 of 1/1.39. They were relatively insensitive to changes in inter-electrode distance, or to partial anaesthetization with tetrodotoxin. In fibres treated with diphtheria toxin 6-8 days previously, to induce paranodal or segmental demyelination, threshold minima were found both at nodes and in internodal regions generating inward membrane current. In these fibres strength-duration curves were of the same general form as at normal nodes, but with strength-duration time constants increased at widened nodes (up to 350 microseconds) and at excitable internodes (600-725 microseconds). Comparison with the computer model indicated that these changes were most likely due to exposure of axon membrane with a time constant much longer than that of the normal nodal membrane. In none of the demyelinated fibres examined have we found any evidence of hyperexcitability.

Animals↗
PubMed1983

The strength-duration relationship for excitation of myelinated nerve: computed dependence on membrane parameters.

Thresholds to applied current pulses have been determined for the myelinated nerve model of Goldman & Albus (1968). Strength-duration curves have been plotted, and compared with three strength-duration equations that have been proposed in the past. The simple, linear relation between stimulus charge and stimulus duration proposed by Weiss (1901) provided the best fit to the computed data. The effects on the strength-duration relationship of changes in twelve parameters of the model were determined and expressed in terms of the strength-duration time constant and rheobasic current. The rheobase depended primarily on conductances, whereas the strength-duration time constant depended on the electrotonic time constant and also on the rate of sodium activation. The model predicts strength-duration curves of the same form, for extracellular or intracellular stimulation where the external resistance is low and uniform. Tripolar stimulation, with anodes over adjacent rather than remote nodes, is predicted to result in much shorter strength-duration time constants, but with a similar sensitivity to nodal membrane parameters. The limitations of strength-duration measurements on myelinated nerves are discussed in the light of these simulations.

Action Potentials↗
PubMed1982

Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline.

The changing electrical and morphological properties of demyelinating and remyelinating nerve fibres have been studied in rat ventral roots after intrathecal injection of lysophosphatidyl choline (LPC). The spatial distribution of electrical excitability within the lesion has been studied in undissected single fibres using high-resolution longitudinal current analysis. The distribution of excitability has been correlated with the ultrastructure of the fibres and with the distribution of the surrounding Schwann cells. Demyelinated axolemma was initially not excited, but conduction across demyelinated internodes appeared progressively from the 4th day after LPC injection. Conduction was never continuous, but proceeded via new foci of inward membrane current as early as 4 days after LPC injection, i.e. 3 days before the onset of remyelination. It is suggested that these foci (termed phi-nodes to distinguish them from the nodes of Ranvier distributed along myelinated nerve fibres) are precursors of nodes of Ranvier, and may indicate aggregates of sodium channels which form along the demyelinated axolemma prior to remyelination.

Animals↗
PubMed1981

Conduction in regenerating dorsal root fibres.

Rat dorsal roots were crushed and recordings of compound action potentials and single fibre longitudinal currents were made 12-85 days later from the regenerating portions. Maximum conduction velocities rose from 1.3 m/s at day 10 to 25.7 m/s by day 41 and single fibre velocities varied from 1.2 m/s at 12 days postcrush to 23.8 m/s at 85 days. Many fibres appeared to conduct continuously in the early stages, although the resolution of the technique was insufficient to exclude saltatory conduction over short internodes. Two fibres showed internodes of about 200 microns at 9 and 13 days of regeneration, suggesting that "nodal" regions may be formed before significant myelination. At 27 days post-crush and later, internodes were 300-425 microns in length. Many regenerating fibres had branches, both retrograde and orthograde. Reduced conduction velocities in rostral portions of regenerating fibres suggested tapering.

Animals↗
PubMed1981

The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.

1. 4-Aminopyridine (4AP) and tetraethylammonium ions (TEA), which block voltage-dependent potassium channels in other nerve membranes, have been used to study nerve conduction in fibres of normal rat spinal roots and those demyelinated with diphtheria toxin. The pharmacological actions have been compared with those of temperature. 2. Both TEA and 4AP increased the amplitude and duration of the monophasically recorded compound action potentials of non-myelinated fibres in normal rat dorsal roots. Enhancement of the action potential amplitude by 4AP was maximal near 1 mM, and was not readily reversed by washing. At concentrations up to 50 mM the action of TEA was weaker and reversible. 3. In normal dorsal and ventral roots TEA (20 mM) and 4AP (5 mM) had only a mildly depressant action on the compound action potentials of myelinated fibres. Whereas the slight reduction in peak amplitude and increase in width was also found in a single fibres treated with TEA, none was discerned in single fibres exposed to 4AP over a wide temperature range. 4. It is concluded that voltage-dependent potassium channels occur in significant numbers in mammalian non-myelinated fibres, but not at nodes of Ranvier. 5. Spinal roots previously treated with diphtheria toxin to cause demyelination were studied by longitudinal current analysis. Fibres affected by diphtheria toxin had a late phase of outward current, either restricted to nodes or, in the case of continuous conduction, distributed along internodes, and this outward current was specifically blocked by 4AP. 6. Both 4AP and TEA increased the temperature at which conduction block occurred in most single demyelinated fibres, so that in some cases fibres blocked at physiological temperatures were enabled to conduct. 4AP was more potent than TEA, but less consistent in its effect. 7. It is concluded that potassium channels are present at widened nodes and in internodal axolemma exposed by demyelination. Their presence enables TEA and 4AP to overcome conduction block in some demyelinated nerve fibres.

4-Aminopyridine↗
PubMed1980

Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres.

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres. Although the particular substance then used, a scorpion venom, was not a suitable therapeutic agent, we suggested that other drugs, with similar but milder effects on the action potential, might be effective in the symptomatic treatment of multiple sclerosis. We now report some encouraging results obtained with 4-amino-pyridine (4AP), a substance which blocks the voltage-dependent potassium current in squid giant axons. The use of a potassium-blocking agent to prolong action potentials may seem surprising because we previously found tetraethylammonium chloride (TEA), another potassium blocker, ineffective on normal rat myelinated fibres, and two recent voltage-clamp studies have confirmed that mammalian nodes have few, if any, potassium channels. On the other hand, 4AP strongly potentiates transmitter release from the unmyelinated terminals of rat motor nerves, and the possibility arose that demyelinated axon membrane, which can conduct impulses continuously like an unmyelinated fibre, might further resemble its unmyelinated terminals by responding to 4AP. In testing this hypothesis, we have found that both TEA and 4AP prolong action potentials of demyelinated and unmyelinated fibres, and both facilitate conduction in fibres blocked by demyelination. 4AP is effective at lower concentrations, and is the more promising for clinical use, as it has already been used with beneficial effects in the treatment of Eaton-Lambert syndrome and myasthenia gravis.

Action Potentials↗
PubMed1978

The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination.

1. Longitudinal action currents were recorded from single undissected myelinated nerve fibres in intact, perfused ventral roots of normal rats and ones treated with diphtheria toxin to produce demyelination. 2. Closely spaced recording electrodes (120 micron), signal averaging and the use of a calibrating current throught the root permitted membrane currents to be determined over 240 micron lengths of nerve. Contour plotting was used to plot membrane current density as a function of space and time. 3. The previous result of Rasminsky & Sears (1972) of delayed saltation in demyelinated nerve fibres was confirmed. 4. In addition a new phenomenon of continuous conduction was observed, along distances of up to 1 1/2 times the afferent internodal distance. The continuous spatial distribution of inward current in these cases showed that electrical excitability was distributed along the internodes. 5. Internodal excitability was also revealed in demyelinated fibres by extra foci of inward current judged to be internodal on the basis of the spacing of the other (nodal) foci. 6. Continuous conduction occurred at velocities in the range of 1.1-2.3 m/sec or roughly 1/20th-1/40th of the velocities expected for normal stretches of the same fibres. 7. The continuous conduction was attributed to conduction along lengths of demyelinated axon. This was supported by estimates of 0.86 and 1.5 muF/cm2 for membrane capacity from the foot of a continuously conducted action potential. 8. The implications of internodal electrical excitability in demyelinated nerve fibres are discussed in relation to (a) recent estimates of the density of sodium channels in intact and homogenized normal nerves, (b) the pathophysiology of demyelinating disease.

Action Potentials↗