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T M Fischer

Publications and source records attributed to T M Fischer.

At least 19 recordsLinked to original sources
PubMed1997

Metaplasticity at identified inhibitory synapses in Aplysia.

Synaptic plasticity is an important feature of neural networks involved in the encoding of information. In the analysis of long-term potentiation and long-term depression, several examples have emerged in which this plasticity is itself modulated. This higher-order form of plasticity has been referred to as 'metaplasticity', a modification of synapses reflected as a change in the ability to induce or maintain plasticity. These observations raise the question of the possible advantage of regulating the intrinsic plastic properties of a synapse. The neural circuit mediating the siphon withdrawal reflex in Aplysia provides a useful network in which to examine this question directly. Inhibitory synapses in this circuit (from L30 neurons) exhibit a variety of forms of activity-dependent short-term synaptic enhancement which contribute to dynamic gain control in the siphon withdrawal reflex. Here we report that tail shock, an extrinsic modulatory input of known behavioural relevance, induces differential metaplasticity at this synapse, attenuating its ability to exhibit short-term synaptic enhancement after presynaptic activation (augmentation and post-tetanic potentiation), while leaving intact its capacity for enhancement during activation. This attenuation of inhibition at the synaptic level seems to mediate comparable attenuation of inhibitory modulation at both network and behavioural levels.

Animals↗
PubMed1997

Multiple overlapping processes underlying short-term synaptic enhancement.

Recently there have been exciting advances in understanding the mechanisms and functional roles of a form of short-term synaptic enhancement (STE) that results from an activity-dependent accumulation of Ca2+ in the presynaptic terminal. This form of STE is composed of at least four processes: fast-decaying facilitation (FI), slow-decaying facilitation (F2), augmentation (AUG) and post-tetanic potentiation (PTP). Recent results suggest that these processes can now be distinguished mechanistically by the site of their induction within the presynaptic terminal: FI and F2 appear to be induced by a rapid, high concentration of Ca2+ at or near the site of exocytosis, whereas AUG and PTP seem to be induced by lower levels of Ca2+ with slower kinetics, possibly within the core of the terminal. STE is highly conserved across diverse species, and appears to serve as a flexible mechanism for temporal information processing in systems ranging from peripheral motor control to higher cortical integration.

Animals↗
PubMed1997

Activity-dependent potentiation of synaptic transmission from L30 inhibitory interneurons of aplysia depends on residual presynaptic Ca2+ but not on postsynaptic Ca2+.

Activity-induced short-term synaptic enhancement (STE) is a common property of neurons, one that can endow neural circuits with the capacity for rapid and flexible information processing. Evidence from a variety of systems indicates that the expression of STE depends largely on the action of residual Ca2+, which enters the presynaptic terminal during activity. We have shown previously that a Ca2+-dependent STE in the inhibitory synapse between interneurons L30 and L29 in the abdominal ganglion of Aplysia californica has a functional role in regulating the gain of the siphon withdrawal circuit through facilitated recurrent inhibition onto the L29s. In the present paper, we further explore the role of Ca2+ in L30 STE by examining two basic issues: 1) What is the role of residual presynaptic Ca2+ in the maintenance of L30 STE? We examine this question by first inducing STE in the L30s then rapidly buffering presynaptic free calcium through the use of the photoactivated Ca2+ chelator diazo-4, which was preloaded into the L30 neurons. Three forms of STE in the L30s were examined: frequency facilitation (FF), augmentation (AUG), and posttetanic potentiation (PTP). In each case, the activation-induced enhancement of the L30 to L29 synapse was reduced to preactivation levels at the first test pulse following photolysis of diazo-4. 2) What is the role of postsynaptic Ca2+ in the induction of L30 STE? We examine whether there is a postsynaptic requirement of elevated Ca2+ for the induction of L30 STE by first injecting the calcium chelator bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) into the postsynaptic cell L29 (at levels sufficient to block transmitter release from the L29s), to prevent any increase in postsynaptic intracellular Ca2+ that may occur during L30 (presynaptic) activation. We found that BAPTA injection did not effect either the induction or the time course of FF, AUG, or PTP in the L30s. Taken collectively, our data indicate that all forms of STE in the L30s depend on presynaptic free cytosolic Ca2+ for their maintenance but do not require the elevation of postsynaptic Ca2+ for their induction.

Animals↗
PubMed1995

Cutaneous activation of the inhibitory L30 interneurons provides a mechanism for regulating adaptive gain control in the siphon withdrawal reflex of Aplysia.

The functional role of inhibition in the neural network underlying the siphon withdrawal response (SWR) of Aplysia was assessed by examining a recurrent circuit comprised of identified inhibitory interneurons (L30s), and excitatory interneurons (L29s). We previously showed that activity-dependent potentiation of the L30 inhibitory synapse onto L29 can regulate the net excitatory input elicited by tactile siphon stimulation onto siphon motor neurons (LFS cells) (Fischer and Carew, 1993a). To explore the functional significance of L30 potentiated inhibition, we have examined how a behaviorally relevant stimulus that activates the L30 interneurons modulates the SWR circuit. Utilizing a reduced preparation, we show that weak tactile stimulation of the tail strongly activates the L30s, and leads to significant potentiation of the L30 synapse. Next, we demonstrate that similar weak tail stimulation produces significant inhibition of siphon tap-evoked responses in both L29 interneurons and LFS motor neurons. We further show that this form of inhibition is transient, having a time course of approximately 60 sec. Finally, we directly tested the role of the L30s in mediating this form of inhibition by hyperpolarizing two (of three) L30 interneurons during tail stimulation. L30 inactivation significantly attenuated tail stimulation-induced inhibition of siphon-evoked input to both L29 interneurons and LFS motor neurons. Based on these results, we suggest that L30-potentiated inhibition may have an important adaptive role in optimizing the signal-to-noise ratio for activation of the SWR circuit by providing stabilization of SWR responsiveness under a wide range of environmental conditions.

Adaptation, Physiological↗
PubMed1993

Bending stiffness of lipid bilayers: IV. Interpretation of red cell shape change.

Two mechanisms are operative when the resting shape of human red cells is changed into an echinocyte or a stomatocyte. The first (bilayer couple) is a differential change in the surface area of the two monolayers. It rests on the two-dimensional isotropic elasticity of the two monolayers and their fixed distance. The second (single layer) is a change in the average cone angle of the molecules comprising a monolayer. It rests on the intrinsic bending elasticity of each single layer. With a few exceptions the first mechanism has been quoted to interpret experimentally observed shape changes. To reconsider this preference two types of spontaneous curvatures (in bilayer couple bending and in single-layer bending) are defined. It is shown that (a) disregarding the single-layer mechanism is not justified and (b) there is too little basic information for quantitative interpretations of shape change.

Elasticity↗
PubMed1993

Activity-dependent potentiation of recurrent inhibition: a mechanism for dynamic gain control in the siphon withdrawal reflex of Aplysia.

The siphon withdrawal response (SWR) of Aplysia supports several forms of learning that are under both excitatory and inhibitory control. Here we examine the role of interneuronal processing on the regulation of siphon responses, with an emphasis on the role of inhibition. We focus on the recurrent circuit formed by the excitatory interneuron L29 and the inhibitory interneuron L30, and show that this circuit provides a mechanism for use-dependent regulation of excitatory input onto siphon motor neurons. We utilized a reduced preparation in which input to the SWR circuit was elicited by taps applied to the siphon; tap-evoked EPSPs were measured in LFS siphon motor neurons. We first show that L29 is an important source of excitatory input to LFS motor neurons: voltage-clamp inactivation of a single L29 (out of five) results in a significant reduction of tap-evoked EPSPs. Next, we demonstrate that direct intracellular activation of L29, surprisingly, produces transient inhibition of evoked input to motor neurons that lasts up to 40 sec. We then provide several lines of evidence that the mechanism of L29-induced inhibition is through the recruitment and potentiation of recurrent inhibition from L30: (1) L29 activation results in reduced tap-evoked responses of other (nonactivated) L29s; (2) direct activation of L30 mimics the inhibitory effects produced by L29 activation (LFS neurons receive no direct synaptic input from L30); and (3) the L30 IPSP is significantly potentiated as a result of its own activity, whether produced directly (by L30 activation) or indirectly (through L29 activation). This IPSP potentiation has the same time course as L29-induced inhibition of motor neuron responses. Thus activity-dependent potentiation of L30 transmission can inhibit motor neuron responses, in part through inactivation of the L29 interneuronal pool. Finally, we propose that L29-L30 interactions provide a mechanism for dynamic gain control in the SWR.

Animals↗
PubMed1992

Bending stiffness of lipid bilayers. I. Bilayer couple or single-layer bending?

To describe the resistance of a bilayer to changes in curvature two mechanisms are distinguished which are termed bilayer couple bending and single-layer bending. In bilayer couple bending, the resistance arises from the 2-D isotropic elasticity of the two layers and their fixed distance. Single-layer bending covers the intrinsic bending stiffness of each monolayer. The two mechanisms are not independent. Even so, the distinction is useful since bilayer couple bending can relax by a slip between the layers from the local to the global fashion. Therefore, the bending stiffness of a bilayer depends on the time scale and on the extent of the deformation imposed on the membrane. Based on experimental data, it is shown by order of magnitude estimates that (a) the bending stiffness determined from thermally induced shape fluctuations of almost spherical vesicles is dominated by single-layer bending; (b) in the tether experiment on lipid vesicles and on red cells, a contribution of local bilayer couple bending can not be excluded; and (c) at the sharp corners at the leading and the trailing edge of tanktreading red cells, local bilayer couple bending appears to be important.

Biomechanical Phenomena↗
PubMed1992

Is the surface area of the red cell membrane skeleton locally conserved?

The incompressibility of the lipid bilayer keeps the total surface area of the red cell membrane constant. Local conservation of membrane surface area requires that each surface element of the membrane skeleton keeps its area when its aspect ratio is changed. A change in area would require a flow of lipids past the intrinsic proteins to which the skeleton is anchored. in fast red cell deformations, there is no time for such a flow. Consequently, the bilayer provides for local area conservation. In quasistatic deformations, the extent of local change in surface area is the smaller the larger the isotropic modulus of the skeleton in relation to the shear modulus. Estimates indicate: (a) the velocity of relative flow between lipid and intrinsic proteins is proportional to the gradient in normal tension within the skeleton and inversely proportional to the viscosity of the bilayer; (b) lateral diffusion of lipids is much slower than this flow; (c) membrane tanktreading at frequencies prevailing in vivo as well as the release of a membrane tongue from a micropipette are fast deformations; and (d) the slow phase in micropipette aspiration may be dominated by a local change in skeleton surface.

Biomechanical Phenomena↗
PubMed1989

Cross bonding and stiffening of the red cell membrane.

Cross bonding and stiffening of the human red cell membrane was studied using treatments with SH, amino, and carboxyl reagents, oxidizing and denaturing treatments and acidification. Membrane cross bonding was initiated when, after red cell treatment, opposite areas of the cytoplasmic face of the red cell membrane were brought into contact by cell shrinking. Membrane cross bonding was detected by light microscopy when this contact persisted upon swelling the cells in a hypotonic medium. Membrane stiffening was recorded as a decrease in elongation of red cells in the shear field of a viscous dextran solution. No correlation was found between membrane cross bonding and membrane stiffening. The results are explained by the existence of two modifications of spectrin, type I causing solely membrane stiffening, type II causing membrane cross bonding as well as membrane stiffening. The amino and carboxyl reagents caused only type I modification. The other treatments caused both types of modification although with varying proportions. The results support the previously suggested mechanism of membrane cross bonding which involves a rearrangement of spectrin similar to denaturation by heat or urea, a decrease in associations within the membrane skeletal network, and a lateral aggregation of membrane proteins. These changes are proposed to occur by the type II modification. The data further substantiate the membrane stiffening effect of inter- and intra-molecular cross linking of spectrin which is identified with the type I modification. Finally, hypotheses are presented concerning the mechanism of membrane stiffening due to type II modifications of spectrin.

Cross-Linking Reagents↗
PubMed1989

Mechanical hemolysis of cross-bonded red cells in the microcirculation.

In favic crises the effective surface area of red cells is reduced by a mechanism called membrane cross bonding (Fischer et al., Brit. J. Haematol. 59, 159, 1985). In these crises massive intravascular hemolysis is observed the cause of which is unknown. One possibility is mechanical hemolysis of cross-bonded red cells that cannot negotiate the microcirculation due to their decreased effective surface area. To investigate this possibility critical phenomena of red cell behavior in the microcirculation were studied using Laplace's law. In model calculations an idealized vessel geometry was used: a funnel in which the angle of the conical part and the radius of the cylindrical part were varied. A map of these two parameters was established showing where red cells either enter the funnel or get stuck and where they would hemolyse under a pressure difference of 3 mm Hg. Adopting a teleological point of view it was assumed that red cell and vessel geometry are mutually adapted. Based on this assumption those combinations of the two parameters cone angle and radius were found that allow the passage of the complete population of normal red cells without hemolysis. Assuming a reduction in red cell surface area similar to that observed in favic crises it was found that only a small portion of the population would hemolyse. Therefore, mechanical hemolysis may not suffice to explain the observed intravascular hemolysis.

Capillary Resistance↗
PubMed1988

Development of the optic nerve of the opossum (Didelphis virginiana).

The development of the optic nerve of a marsupial, the North American opossum, was examined in 24 animals from postnatal days 5 to 78 (P5-P78): gestation is 13 days. The estimated number of axons increased from 24,000 at P5, to 267,000 at P27, approximately 2.7 times the mean number in the adult. Following P27, axon numbers decreased rapidly to 140,000 at P40, then decreased more slowly, attaining adult values between P50 and P59. Thus, the opossum is similar to placental mammals examined in evidencing an overproduction and later attenuation to adult values in the number of axons in the optic nerve during development. Monocular enucleation of 3 animals at P17, 10 days before peak axon counts, resulted in a mean population increase of 24,000 (range 19,000-30,000) above the normal adult mean. Additionally, a 4th animal monocularly enucleated on P7, 3 days prior to the arrival of migrating fibers to central target sites, had a similar value of 26,500 supernumerary axons. Our findings in the opposum, when coupled with previous reports in other mammals, suggest that binocular interactions during development account only for optic nerve axon loss approximately equal in magnitude to the ipsilateral projection from one eye.

Aging↗
PubMed1988

Role of spectrin in cross bonding of the red cell membrane.

Membrane cross bonding--an adhesion between opposing areas of the cytoplasmic face of the red cell membrane--was achieved by treating red cells with heat, diamide, N-ethymaleimide, urea, or by ATP depletion in conjunction with cell shrinking. Membrane cross bonding could be recognized by the shape of the cells upon swelling. Quantitated by the percentage of cross-bonded red cells the effectivity of the treatments decreased in the order given above. Cross bonding was hardly reversible by reducing the diamide-induced S-S bonds with dithioerythritol. The effect of heat and urea treatment as well as ATP depletion was partly reversible. Transmission electron micrographs of the cross-bonded region showed basically parallel membranes. The distance between the respective phospholipid bilayers varied between 40 and 120 nm from cell to cell. Hb-free ghosts prepared from diamide-treated red cells could also be cross bonded. The following conclusions are drawn: spectrin provides the molecular cross link in membrane cross bonding. Aggregation and enrichment of spectrin in the cross-bonded region are probably involved in membrane cross bonding.

Adenosine Triphosphate↗
PubMed1987

A circulation model for teaching fluid dynamics in laboratory courses in physiology.

Medical students in Germany do not usually have a strong enough basis in physics to understand the mechanical and fluid dynamic problems involved in the physiology of the circulation. To alleviate this situation we developed a circulation model for use in laboratory courses in physiology. The following parameters can be varied: stroke volume, heart rate, systemic filling pressure, compliance of the arterial system (Windkessel), and total peripheral resistance. Arterial and venous pressure are recorded as a function of time. The following points are worked out by the students by adjusting the parameters of the model and by calculation: static equilibrium, transient and steady state in flow, compliance of the arterial and venous system, arteriovenous pressure difference, cardiac output, total peripheral resistance, regulation of cardiac output, pulse pressure amplitude, volume stored periodically in the arterial Windkessel, diastolic pressure decay of arterial pressure, diagnosis of arterial hypertension at different Windkessel compliances.

Biophysics↗
PubMed1986

Transcellular cross bonding of the red blood cell membrane.

When red blood cells are osmotically shrunk, opposing regions of the inner membrane surface touch each other in the dimple area. In normal red cells such a mechanical contact is undone by reswelling the cells. When the cells are treated with the SH reagents diamide or N-ethylmaleimide, or simply heated to temperatures between 42 and 48 degrees C such a mechanical contact can be made permanent by a process termed 'membrane cross bonding'. Cross bonding also occurred when the cells were treated before mechanical contact was established. The bridge between the two cross-bonded membrane regions may be assumed to be formed by membrane skeletal material. Membrane bridges become visible microscopically when the cells are swollen. These bridges are strong enough to resist the membrane tensions occurring at osmotic lysis. Bridged red cells can be a useful tool in rheology, since they are deformable but cannot adapt to shear flows by membrane tank treading.

Cross-Linking Reagents↗
PubMed1985

Membrane cross bonding in red cells in favic crisis: a missing link in the mechanism of extravascular haemolysis.

Red cells of G6PD (D-glucose-6-phosphate:NADP+ 1-oxidoreductase; G6PD) deficient (Mediterranean variant) subjects were studied during a fava bean haemolytic crisis. Two representative cases are described. In Case 1, haemolysis was still going on. In more than 50% of the red cells the Hb was confined to one part of the cell, leaving the other part as transparent as a Hb-free ghost. In this part the membranes appeared tightly bonded because swelling did not peel apart the bonded membrane areas. This feature is defined as membrane cross bonding (MCB). In Case 2, haemolysis had terminated and MCB-cells were less than 1%. MCB was reproduced in vitro by incubating G6PD-deficient whole blood with 1 mM divicine for up to 10 h. Subsequent shrinkage of red cells in hypertonic plasma (400 mOsm) resulted in the rapid formation of MCB. Membrane modifications by divicine, contained in fava beans, followed by osmotic shrinkage in the kidney and/or squeezing in the microcirculation are proposed as the cause of MCB during the favic crisis. MCB reduces the effective surface area of red cells. This is a plausible cause for sequestration by the reticulo-endothelial system. Intravascular haemolysis observed in favic crisis cannot be explained by mechanical forces, but it is possible that the effective surface area is reduced by MCB to such an extent that red cells lyse osmotically.

Child↗
PubMed1984

Flow behaviour of rigid red blood cells in the microcirculation.

Flow behaviour of rigid (diamide treated) red blood cells (RBC) was investigated in anaesthetised rats and isolated rat mesentery, supplemented by pressure-flow curves in small bore glass tubes. It was shown that (1) Diamide treated cells, the shear modulus of which is increased, were not eliminated from the circulation of rats within an experimental time of 4 h. (2) At normal arterial pressure, an exchange of native for diamide treated red blood cells only slightly reduced RBC flow velocity in capillaries of the mesentery of anaesthetised rats. (3) Flow velocity of stiffened red blood cells was drastically reduced at low driving pressure (hypotension). Many capillaries became irreversibly clogged and flow did not resume with normalisation of the arterial blood pressure. (4) In the capillaries of the isolated mesentery, no difference in resistance to flow was observed between treated and control cells as long as steady state velocities were compared. This is in accordance with results obtained in glass tubes above wall shear stresses of 0.05 Pa. At stenoses, however, where RBC's undergo transient deformations, the passage times of treated cells were longer than those of untreated cells. From this it is concluded that not only the elastic properties but also the viscous properties of the red cell membrane are changed by diamide treatment and that the dynamic response of the red cell during transient deformations may limit the ability of the cell to negotiate the microcirculation.

Animals↗