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Dive into the research topics where Stephen G. Waxman is active.

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Featured researches published by Stephen G. Waxman.


Developmental Brain Research | 1982

Rat optic nerve: Electrophysiological, pharmacological and anatomical studies during development

Robert E. Foster; Barry W. Connors; Stephen G. Waxman

Changes in conduction properties and in morphology were studied during rat optic nerve growth from birth (when no myelin is present and the glia have not differentiated) to adulthood (when the optic nerve is essentially 100% myelinated). Myelination begins around the sixth postnatal day and proceeds rapidly so that 85% of the fibers are myelinated at 28 days of age. Mean diameter of optic nerve axons remains about 0.2 micron for the first week and then increases rapidly if the fiber is being myelinated. Those axons not being myelinated remain about 0.2-0.3 micron in diameter. At birth the compound action potential has a single negative peak and a conduction velocity of about 0.2 m/s. The increase in conduction velocity prior to myelination is considerably greater than can be accounted for on the basis of increase in axonal diameter. There is no clear step increase in the velocity of the shortest latency peak correlated with the onset of myelination. During myelination the compound action potential develops multiple short latency components, which evolve into the adult-like 3 component compound action potential by 3-4 weeks of age. Durations of the relative refractory period and supernormal period decrease as age increases, but are not related to myelination in a simple manner. Sodium appears to be the only significant carrier of inward current at all ages. A measureable calcium conductance is not present at any age. Voltage-dependent potassium conductance contributes to the compound action potential at all ages, but the response to 4-aminopyridine in rapidly conducting fibers is apparently smaller than that in slowly conducting fibers. These results show that conduction can occur before myelination or the differentiation of glial cells. Moreover, changes in conduction velocity do not depend entirely on myelination or increases in axonal size. Finally, these results suggest a reorganization of axonal membrane properties during the development of rat optic nerve.


Proceedings of the Royal Society of London. Series B, Biological sciences | 1982

Regenerating Mammalian Nerve Fibres: Changes in Action Potential Waveform and Firing Characteristics Following Blockage of Potassium Conductance

J.D. Kocsis; Stephen G. Waxman; C. Hildebrand; J. A. Ruiz

Extracellular application of potassium channel blocking agents is known to increase the amplitude and duration of the compound action potential in non-myelinated and demyelinated axons, but not in mature mammalian myelinated fibres. In the present study we used intra-axonal and whole nerve recording techniques to study the effects of the potassium channel blocking agent 4-aminopyridine (4-AP) on regenerating rat nerve fibres. Our results indicate that early regenerating (premyelinated) axons show considerable broadening of the action potential after 4-AP application and late regenerating (myelinated) axons give rise to burst activity following a single stimulus after 4-AP application. 4-AP did not affect spike waveform or firing properties of normal mature sciatic nerve fibres. These results demonstrate the importance of potassium conductance in stabilizing firing properties of myelinated regenerating axons.


Brain Research | 1983

Regional node-like membrane specializations in non-myelinated axons of rat retinal nerve fiber layer

C. Hildebrand; Stephen G. Waxman

The axons in the nerve fiber layer (NFL) of the adult rat retina were examined by transmission electron microscopy. NFL axons range in size from 0.12 to about 2.0 microm, with a peak at 0.3-0.4 microm. In addition to conventional small mitochondria in the NFL axons contain some large ones, which are similar to astrocytic gliosomes. Two types of regional axon membrane specialization are found in the NFL. One of these represents portions of the initial axon segments of retinal ganglion cells. Apart from features typical for initial axon segments in general, a corona of lamelliform, villous or blunt glial processes is always present. The glial processes originate from MUller cells. The other regional axon membrane specialization consists of patches of an electron-dense subaxolemmal undercoating with associated tufts of Miller cell processes. These patches cover a varying but always limited proportion of the axon circumference and their longitudinal extent varies between 0.5 and 5.0 microm. They are clearly distinct from the initial axon segment and from the initial heminode in the optic nerve. Similar undercoated patches in the optic disc axons are apposed by astrocytic processes. It is concluded that rat NFL axons represent an example of central non-myelinated axons with distinct regional membrane specializations, which have some structural characteristics in common with nodes of Ranvier.


Brain Research | 1984

Specificity in central myelination: evidence for local regulation of myelin thickness.

Stephen G. Waxman; Terry J. Sims

The ventral funiculi of normal and X-irradiated 13-day-old rats were studied by electron microscopy. In both tissues, oligodendrocytes form myelin sheaths around multiple axons, with a single oligodendrocyte associated with several axons of different sizes. Despite their origin from the same glial cell, the myelin sheaths are thicker for larger axons. Polyribosomes and rough endoplasmic reticulum are observed in distal oligodendrocyte processes, in proximity to the forming myelin sheaths. These results indicate that myelin sheath thickness is matched to axon size via local mechanisms, and suggest a role of polyribosomes and/or rough endoplasmic reticulum in myelin formation.


Journal of Neurocytology | 1985

Axo-glial relations in the retina-optic nerve junction of the adult rat: electron-microscopic observations

C. Hildebrand; S. Remahl; Stephen G. Waxman

SummaryThe retina-optic nerve junction (ROJ) was examined by electron microscopy in adult rats, with particular emphasis on the unmyelinated-myelinated nerve fibre transition. Both single sections and serial sections were used. The non-retinal part of the ROJ is covered by an extensively folded glia limitans, facing the choroidea, sciera and pia mater. The blood vessels within the ROJ follow a transverse course and are surrounded by unusually wide perivascular spaces with a glia limitans-like outer delimitation. The endothelial cells exhibit numerous pinocytotic vesicles on their abluminal aspect. In the unmyelinated part of the ROJ the axons are embedded in an extensive meshwork of fibrous astrocytic processes. Some unmyelinated axons exhibit patches of axolemmal undercoating with externally associated astrocytic processes. Typical oligodendrocytes are not found, but a few small dark glial cells of unknown identity can be observed. Atypical ensheathment and myelination of axons at this level by ectopic Schwann cells occurred in one case. In the transition segment of the ROJ a pattern similar to that along dysmyelinated axons is observed, including aberrant axo-glial contacts, unusually thin and short myelin sheaths, intercalated unmyelinated segments, distorted myelin termination regions, bizarre paranodes and myelin termination regions without associated nodally differentiated axolemma. Neither sheath length nor number of myelin lamellae is related to axon diameter in the transition region. Axon diameter tends to be somewhat larger at myelinated than unmyelinated levels of the same axon. We suggest that the unusual axo-glial relations in this region are due to a deficient proliferation and differentiation of oligodendroglial cells, and that the pattern of glial ensheathment in the ROJ might be a consequence of the locally deficient blood-brain barrier.


Brain Research | 1985

Myelin sheath remodelling in regenerated rat sciatic nerve

C. Hildebrand; J.D. Kocsis; S. Berglund; Stephen G. Waxman

In order to elicit de- and remyelination adult rat sciatic nerves were injected with diphtheria toxin dissolved in phosphate buffered saline (PBS). Control nerves were injected with PBS alone. After survival times of 1–10 weeks, the animals were perfused with glutaraldehyde. Specimens from the injected nerves were processed for light microscopic (LM) examination of teased fibres or for electron microscopic (EM) examination of longitudinal thin sections. LM examination of teased fibres after survival times of 6–10 weeks, showed that most remyelinated internodes are 150–300 μm long. In addition, some exceptionally short Schwann cell sheaths, with lengths of 15–150 μm, occur intercalated between conventional remyelinated internodes. EM analysis of thin sections showed that axonal evaginations penetrate in between the terminating myelin lamellae in fibres with nodal widening and/or paranodal demyelination, at early stages of demyelination. Such alterations are not present in relation to myelin sheaths formed during remyelination, which commences about 3 weeks after injection. In addition, some scattered contracted Schwann cell sheaths, which may be as short as 5–10 μm, occur at all stages. These are more frequent shortly after onset of remyelination than at later stages, and they are either composed of a cytoplasmic investment bordered by heminodes, or a more or less distorted myelin sheath bordered by nodes of Ranvier. This picture is very similar to the myelin sheath remodelling observed in regenerated rat sciatic nerves, and in some developing nerves with a mismatch between nerve growth and internodal elongation. It is concluded that a myelin sheath remodelling occurs in deand remyelinated rat sciatic nerve, presumably as a result of the lack of longitudinal growth.


Neuroscience Letters | 1987

Functional differences between 4-aminopyridine and tetraethylammonium-sensitive potassium channels in myelinated axons

J.D. Kocsis; Douglas L. Eng; T.R. Gordon; Stephen G. Waxman

Intracellular recordings from rat sciatic nerve fibers showed that the potassium channel blocking agents 4-aminopyridine (4-AP) and tetraethylammonium (TEA) had different effects on action potential waveform. When applied alone, TEA did not appreciably alter the waveform of an individual action potential, whereas 4-AP application resulted in action potential broadening and, in some axons, repetitive firing. A prolonged afterhyperpolarization which was blocked by TEA occurred subsequent to repetitive firing. These results indicate the presence of at least two pharmacologically defined potassium channels in mammalian peripheral nerve fibers. The 4-AP-sensitive potassium channels are important for rapid action potential repolarization and the TEA-sensitive potassium channels may serve to modulate axonal excitability during repetitive firing.


Journal of the Neurological Sciences | 1979

Lysophosphatidyl choline-induced focal demyelination in the rabbit corpus callosum ☆: Electron-microscopic observations

Stephen G. Waxman; J.D. Kocsis; K.C. Nitta

The local application of lysophosphatidyl choline (LPC) by microinjection into the region of the corpus callosum of the rabbit produced demyelinating lesions. The lesions were assessed histologically using the Luxol fast blue myelin stain and the Holmes silver nitrate stain for the axis cylinders. Survival times for the animals ranged from 7 to 14 days. The center of the lesion was marked by infiltration of macrophages and necrosis, but the major area of the lesion was characterized by demyelination. By consideration of anatomical factors influencing LPC diffusion and of the appropriate placement of the injection, the entire vertical extent (about 0.5 mm) of the corpus callosum could be demyelinated with minimal amounts of necrosis. Since focal demyelination was possible in the fine caliber axons of the corpus callosum which are anatomically representative of many forebrain fiber systems, and since this fiber system is amenable to chronic physiological investigation, the corpus callosum may serve as an experimental model for morpho-physiological studies of mammalian central demyelinating pathways.


Brain Research | 1984

Impulse conduction in inhomogeneous axons: Effects of variation in voltage-sensitive ionic conductances on invasion of demyelinated axon segments and preterminal fibers

Stephen G. Waxman; Sally L. Wood

Conduction in inhomogeneous axons may be blocked by several mechanisms. Conduction in demyelinated axons may fail since normal internodal membrane is inexcitable, because values of sodium conductance are too low to support impulse conduction. In addition, focal loss of myelin causes increased current leakage which slows or blocks invasion of impulses into the demyelinated zone due to inadequate current density. Similar considerations apply to the invasion of non-myelinated preterminal axons from myelinated parent fibers, where conduction can be blocked as a result of inadequate current density. A cable model of an axon is presented which allows myelinated regions, regions without myelin, and variable length transition zones of redistributed channel densities, to be studied. Action potentials and membrane currents were studied. Computer simulations using this model show that the safety factor for invasion is dependent on temperature. These studies also show that small changes in axon membrane properties, at the transition region between the myelinated zone and the region without myelin, may promote invasion of the region without myelin. In particular, increasing sodium conductance (gNa) or decreasing potassium conductance (gK) promotes invasion. Because of the non-linear behavior of excitable membranes the spatial distribution of channels is shown also to have significant effects on invasion. Thus, relatively small degrees of membrane reorganization may lead to functional changes with respect to the invasion of demyelinated axon regions. Similarly, the properties of the heminode at the distal part of the parent myelinated fiber may determine the invasion characteristics of non-myelinated terminal axons.


Brain Research | 1986

Mammalian optic nerve fibers display two pharmacologically distinct potassium channels

J.D. Kocsis; Thomas R. Gordon; Stephen G. Waxman

A suction electrode recording technique was used to study action potential characteristics of rat optic nerve fibers. Two pharmacologically distinct potassium channels are described. One is sensitive to 4-aminopyridine (4-AP) and the other to tetraethylammonium (TEA). 4-AP application leads to a substantial broadening of the optic nerve action potential, but TEA does not. 4-AP application also elicits a TEA-sensitive post-spike positivity, i.e. an intracellular hyperpolarization. From these results we suggest that the 4-AP-sensitive channel, not the TEA-sensitive channel, is primarily responsible for action potential repolarization of mammalian optic nerve fibers.

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Fuki M. Hisama

University of Washington

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Shirley Ann Gilmore

University of Arkansas for Medical Sciences

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