Halina Meiri

Is synaptic transmission modulated by progesterone

The influence of the gonadosteroid hormone progesterone on synaptic transmission was studied using the frog neuromuscular preparation. Intracellular recording of synaptic potentials revealed enhanced release of acetylcholine from motor nerve terminals exposed to progesterone (3 nM-3 mM). The following effects were observed. An augmented quantal content of evoked release of transmitter; an elevation in synaptic facilitation; and a substantial increase in the rate of spontaneously occurring miniature endplate potentials. It is suggested that synaptic transmission at the neuromuscular junction may be naturally modulated by the physiologically oscillating level of progesterone.

Differentiated neuroblastoma cells are more susceptible to aluminium toxicity than developing cells.

The influence of aluminium (20–50 μg/ml) on neuronal function was examined using electrophysiological techniques and neuroblastoma clone cells which offer a convenient model of differentiating and fully active neurons. Two specific questions were addressed: 1) Can differentiated cells maintain their normal excitable function when exposed to aluminium? 2) Can proper development of electrophysiological properties be achieved in its presence? We report that aluminium caused premature onset of deterioration in fully differentiated cells. Within 4–6 days they depolarized from −29.3+-0.9 mV to levels lower than −15 mV; compound polyphasic action potentials were gradually replaced by slow monophasic spikes before the final loss of excitable properties and structural deformations was noticed. Developing cells followed the normal pattern of differentiation in the presence of aluminium: within 7 days they extended neurites, hyperpolarized and exhibited polyphasic spikes. These results show that neuroblastoma cells are apparently less susceptible to aluminiums toxicity during the process of development than after differentiation. Possible mechanisms by which aluminium may exert its effects are discussed in view of these observations.

The fusogenic substance dimethyl sulfoxide enhances exocytosis in motor nerve endings

Fusion of synaptic vesicles with the surface membrane of the nerve terminal is a key step in synaptic transmission, which normally requires the entry of calcium ions into the cell. We report that this fusion and the subsequent liberation of transmitter can also be induced by the fusogenic substances DMSO (dimethyl sulfoxide) and PEG (poly(ethylene glycol)). Calcium ions and DMSO exhibit a synergistic effect in the fusion of synaptic vesicles with the axolemma, resembling their action on fusion phenomena in liposomes.

Hydrogen ions control synaptic vesicle ion channel activity in Torpedo electromotor neurones

During exocytosis the synaptic vesicle fuses with the surface membrane and undergoes a pH jump. When the synaptic vesicle is inside the presynaptic nerve terminal its internal pH is about 5.5 and after fusion, the inside of the vesicle comes in contact with the extracellular medium with a pH of about 7.25. We examined the effect of such pH jump on the opening of the non‐specific ion channel in the synaptic vesicle membrane, in the context of the post‐fusion hypothesis of transmitter release control. The vesicles were isolated from Torpedo ocellata electromotor neurones. The pH dependence of the opening of the non‐specific ion channel was examined using the fused vesicle‐attached configuration of the patch clamp technique. The rate of opening depends on both pH and voltage. Increasing the pH from 5.5 to 7.25 activated dramatically the non‐specific ion channel of the vesicle membrane. The single channel conductance did not change significantly with the alteration in the pH, and neither did the mean channel open time. These results support the hypothesis that during partial fusion of the vesicle with the surface membrane, ion channels in the vesicle membrane open, admit ions and thus help in the ion exchange process mechanism, leading to the release of the transmitter from the intravesicular ion exchange matrix. This process may have also a pathophysiological significance in conditions of altered pH.

Impaired control of information transfer at an isolated synapse treated by aluminum: is it related to dementia?

Information transfer across an isolated cholinergic synapse exposed to aluminum was investigated using conventional electrophysiological techniques and computer-assisted analysis. Spontaneous and stimulation-induced release of neurotransmitter from frog motor nerve endings was augmented in the presence of aluminum (6-200 micrograms/ml). The release-enhancing effect of aluminum was dose-dependent and it was independent of the concentration of calcium ions in the extracellular solution. These results indicate that aluminum at concentrations similar to those found in the diseased brain of demented patients modulates synaptic transmission.

Aluminum Ingestion — Is it Related to Dementia?

Elevated levels of aluminum in brain tissue have been found in demented patients with Alzheimers disease, with ALS-PD complex of Guam and with dialysis encephalopathy. A possible etiological relationship between enhanced aluminum exposure and impaired mental function was suggested both for ALS-PD of Guam (a region where high contents of aluminum in water are found) and for dialysis encephalopathy which appears in dialyzed patients exposed to high doses of aluminum in medications and in dialysate fluid. The role of aluminum in Alzheimers disease is not known as is the question of life-long aluminum accumulation in healthy human beings. In this review we have limited ourselves to the issue of oral aluminum ingestion and the possible neurotoxic consequences of such exposure. The following topics are summarized: 1. Physiological mechanisms involved in ingestion and intestinal absorption of aluminum and the influences of pH and available organic complexing agents on these processes. 2. Effects of an aluminum-enriched diet on behavior and on brain metabolism. 3. Dietary sources of aluminum and elevated loads of this substance due to prolonged intake of aluminum-containing medications. The main conclusion of this summary is that aluminum is absorbed and may accumulate in different organs in both adults and infants. Two groups seem to be at particular risk for aluminum related toxicity: people with chronic renal failure treated with aluminum-containing medications and pre-term infants fed on aluminum containing formulate. It seems probable that at least upon short term exposure the healthy human body can defend itself adequately from aluminums toxic effects. However, not enough information is available on possible effects of life-long exposure to aluminum in the environment, diet and medications, which over decades may lead to accumulation of this substance with expressions of toxicity. Therefore, the question of aluminums relevance to dementive diseases cannot yet be adequately answered.

The difference in shape of spontaneous and uniquantal evoked synaptic potentials in frog muscle.

1. Spontaneous and stimulation‐induced uniquantal synaptic activity at the frog cutaneous pectoris muscle, treated with neostigmine, was recorded by focal extracellular microelectrodes. A monoexponential curve was fitted to the decay of each synaptic response. 2. A highly significant positive relationship was found between the amplitude and the decay time constant of spontaneous extracellular miniature endplate potentials (MEPPs(o)), whereas the relationship displayed by evoked uniquantal extracellular endplate potentials (EPPs(o)) was only slightly greater than zero. 3. The difference did not stem from changes in the muscle membrane conductance or from inclusion of outstanding MEPPs(o) formed as a result of the block of acetylcholinesterase. 4. The dependence of the rise time on the amplitude was also stronger in MEPPs(o) than in EPPs(o). 5. In the absence of neostigmine, MEPPs(o) exhibited a positive correlation between decay time constant and amplitude, while EPPs(o) did not show such a correlation. 6. In view of previously published models of transmitter release, it is suggested that spontaneous secretion of quanta occurs both within and outside the active zones facing postsynaptic areas of variable receptor density.

Effects of aluminium on electrical and mechanical properties of frog atrial muscle

1 The effects of aluminium on membrane ionic currents were studied in single cardiac myocytes. Most of the work was done on frog atrial cells, but some experiments were also carried out on single cells isolated from rabbit ventricles and atria. 2 The effects of aluminium on the force of contraction of frog atrial trabeculae were also investigated. 3 Aluminium was prepared from AlCl3 as a stock 0.5 m solution which has a pH of 3.5. Before each experiment, this solution was added to the control solution, to give a final concentration of 20–100 μg ml−1 aluminium (0.75–3.75 mm AlCl3). The solutions were brought to a pH of 7.4 or 7.6, at which they consist of a mixture of amorphous aluminium hydroxides and a very small amount of soluble ionic aluminium complexes: free aluminium cations (less than 10 pm), aluminohydroxide anions (less than 8 μm). The addition of this suspension reduced the peak inward calcium currents in single rabbit atrial and ventricular cells and in frog atrial cells. In the latter, the peak current was reduced (at + 10 mV) to 45% of control (mean of 9 cells). This effect was reversible upon washout, and was obtained at all membrane potentials, with no shift of the calcium current voltage relationship along the voltage axis. 4 Aluminium also reduced the time‐dependent potassium current IK. This reduction was observed at all membrane potentials. For example, at + 10 mV, the mean reduction of IK (n = 9) was to 69% of the control amplitude. This effect, which was very difficult to reverse, was not due to IK rundown. The fully activated current‐voltage relationships (obtained by standard ‘tail’ analysis) showed that the effect of aluminium was due mainly to a decrease in conductance and not to a shift in the activation range of IK. The mean voltage of half activation was shifted by 8 mV in the depolarizing direction (n = 5). 5 The background potassium current IK1 was also slightly but consistently changed in a complex fashion, with an outward shift at membrane potentials positive to −60 mV. For example, at a membrane potential of −40 mV, the mean shift was by 22 ± 4 pA. At more negative potentials, there was an inward shift in the current amplitudes. For example, for steps to −100 mV the current elicited was larger (more inward) by 53 pA (mean value, n = 10). The reversal potential was slightly shifted (< 10 mV) in the hyperpolarizing direction. 6 The force of contraction of frog atrial trabeculae was altered by aluminium in a complex manner, which showed marked seasonal variation. During most of the year, 50–100 μg ml−1 aluminium caused a biphasic change, with an early small and consistent decrease, followed by a large increase in twitch amplitude. For a short period corresponding to the (local) winter months the sensitivity to aluminium was greatly enhanced. Aluminium 100 μg ml−1 totally abolished contraction (n = 5), while a lower concentration (20 μg ml−1) produced a sustained reduction in the force of contraction. Similar biphasic and seasonal responses have been reported to be induced by lanthanum. 7 The biphasic changes in twitch amplitude were independent of the transmembrane sodium gradient. Aluminium produced the same effects when 90% of the extracellular sodium was replaced by lithium. Caffeine (5 mm) attenuated or even inverted the positive inotropic effect of aluminium. These results imply that aluminium alters the release of calcium from intracellular, caffeine‐sensitive stores. This could be effected either by augmenting the amount released during each activation, and/or by increasing the loading of stores prior to release. 8 These results are discussed in light of several of the previously reported actions of aluminium.

Regulation of Acetylcholine Liberation from Presynaptic Nerve Terminals1

Acetylcholine is liberated from motor nerve terminals either as a molecular leakage or as quantal packages; the latter form of release is responsible for signaling across the neuromuscular synapse. Three main factors determine the number of quanta liberated by the nerve impulse: the degree of presynaptic depolarisation, the frequency of activation of the nerve terminal, and calcium ion concentration in the extracellular medium. These factors seem to act yb changing the free calcium ion concentration [Ca]in in the presynaptic nerve terminal. Thus, processes that change [Ca]in will determine efficiency of synaptic transmission. These processes include fluxes of calcium ions across the presynaptic membrane and reversible translocation by intracellular organelles such as mitochondria, vesicles and soluble molecules. The level of intracellular [Ca] can be changed by ion-containing liposomes. One of the main physiological determinants of the level of transmitter release is potentiation, where the increase in transmitter release is caused by transmembranal processes and intracellular translocation.

Vasopressin produces long-lasting increase in transmitter release

Arginine-vasopressin has a widespread distribution in the nervous system, and has been implicated in cellular and behavioral functions. Its effect on the neuromuscular synapse reveals that it produces long-lasting augmentation in synaptic transmission due to an increase in spontaneous and nerve stimulation evoked quantal transmitter release. No significant postsynaptic effect was detected.