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PubMed1982

Alterations in spontaneous transmitter release by divalent cations after treatment of the neuromuscular junction with beta-bungarotoxin.

1. Spontaneous transmitter release was studied at the frog sartorius neuromuscular junction in the presence of a variety of cations before and after treatment with the specific presynaptic neurotoxin, beta-bungarotoxin (beta-BuTX). 2. Treatment with beta-BuTX produced a maintained increase in spontaneous release, as indicated by the miniature end-plate potential (m.e.p.p.) frequency. It was demonstrated that the m.e.p.p. frequency remained dependent on the extracellular calcium concentration. 3. A 30 mM increase in extracellular sodium chloride produced a reversible increase in frequency only after beta-BuTX treatment, indicating that beta-BuTX had increased the permeability of the presynaptic terminal. 4. Furthermore, several divalent cations other than calcium were shown to either maintain or greatly increase the m.e.p.p. frequency after beta-BuTX treatment (before toxin treatment replacement of calcium by these divalent cations produced only small changes in frequency). The relative effectiveness of the divalent cations tested in increasing spontaneous transmitter release after toxin treatment was Co2+ congruent to Ni2+ greater than Mg2+ greater than Ca2+ congruent to Sr2+ greater than Mn2+. The effect of cobalt, which increased the m.e.p.p. frequency 6.5 times after toxin treatment, was studied in detail.

Acetylcholine↗
PubMed1984

Noncholinesterase actions of an irreversible acetylcholinesterase inhibitor on synaptic transmission and membrane properties in autonomic ganglia.

Superfusion of the organophosphorous acetylcholinesterase inhibitor soman (pinacolyl methylphosphonofluoridate; 0.01-25 microM) produced a dose-dependent reduction of extracellularly and intracellularly recorded synaptic responses in the isolated rat superior cervical ganglia at frequencies of orthodromic stimulation that do not normally produce synaptic depression. The magnitude of depression was dependent upon the frequency of stimulation (0.02-1 Hz), was maintained after the removal of soman from the superfusion solution, and recovered by over 65% during periods of inactivity. The depression of synaptic transmission produced by soman was not dependent upon the inhibition of acetylcholinesterase (AChE) activity by this agent. Transmission was increasingly depressed by doses of soman greater than those needed to inactivate all measurable ganglionic AChE activity. Dose-dependent depression of synaptic transmission in soman also occurred after pretreatment with the irreversible AChE inhibitor diisopropylphosphofluoridate (DFP; 100 microM), which inhibited greater than 98% of the AChE activity in the ganglia. Soman produced a decline in the input resistance, resting potential, spike amplitude, and spike threshold and a reduction in the hyperpolarizing afterpotential. Soman-induced depression of synaptic transmission was not due primarily to a blockade of postsynaptic nicotinic receptors. At concentrations of soman which produced significant depression in transmission, ganglionic depolarization produced by bath-applied carbamylcholine (carbachol) was either slightly depressed or facilitated. In the presence of soman, repetitive focal application of acetylcholine or carbachol did not reveal use-dependent desensitization. Muscarinic antagonists, atropine and pirenzepine, protected against the use-dependent depression of synaptic transmission induced by soman. These results suggest that a principal site of action for soman is at the presynaptic terminal and that this site is sensitive to muscarinic receptor blockade.

Animals↗
PubMed1994

Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism.

Markov kinetic models were used to synthesize a complete description of synaptic transmission, including opening of voltage-dependent channels in the presynaptic terminal, release of neurotransmitter, gating of postsynaptic receptors, and activation of second-messenger systems. These kinetic schemes provide a more general framework for modeling ion channels than the Hodgkin-Huxley formalism, supporting a continuous spectrum of descriptions ranging from the very simple and computationally efficient to the highly complex and biophysically precise. Examples are given of simple kinetic schemes based on fits to experimental data that capture the essential properties of voltage-gated, synaptic and neuromodulatory currents. The Markov formalism allows the dynamics of ionic currents to be considered naturally in the larger context of biochemical signal transduction. This framework can facilitate the integration of a wide range of experimental data and promote consistent theoretical analysis of neural mechanisms from molecular interactions to network computations.

Animals↗
PubMed1989

Cytosolic-free calcium and neurotransmitter release with decreased availability of glucose or oxygen.

Exposing brain slices to reduced oxygen tensions or impairing their ability to utilize oxygen with KCN decreases acetylcholine (ACh) but increases dopamine (DA) and glutamate in the medium at the end of a release incubation. To determine if these changes are due to alterations in the presynaptic terminals, release from isolated nerve endings (i.e. synaptosomes) was determined during histotoxic hypoxia (KCN). KCN reduced potassium-stimulated synaptosomal ACh release and increased dopamine and glutamate release. Since several lines of evidence suggest that altered calcium homeostasis underlies these changes in release, the effects of reducing medium calcium concentrations from 2.3 to 0.1-mM were determined. In low calcium medium, KCN still increased dopamine and glutamate release, but had no effect on ACh release. Hypoxia increased cytosolic-free calcium in both the normal and low calcium medium, although the elevation was less in the low calcium medium. Thus, the effects of histotoxic hypoxia on cytosolic free calcium concentration paralleled those on glutamate and dopamine release. Reducing the glucose concentration of the medium also increased cytosolic-free calcium. The data are consistent with the hypothesis that hypoxia and hypoglycemia increase cytosolic-free calcium, which stimulates the release of dopamine and glutamate, whose excessive release may lead to subsequent cellular damage postsynaptically.

Animals↗
PubMed1992

Cholinergic hyperinnervation in the cerebral cortex of microencephalic rats does not result in muscarinic receptor down-regulation or in alteration of receptor-stimulated phosphoinositide metabolism.

Administration of methylazoxymethanol (MAM; 25 mg/kg) to pregnant rats at gestational day 15 (GD 15) induces a marked reduction of telencephalic areas of the offspring brain. Previous neurochemical studies demonstrated a marked cholinergic hyperinnervation in the cerebral cortex of microencephalic rats. In this study we have evaluated whether this cholinergic hyperinnervation could result in altered functionality of muscarinic receptors. Acetylcholinesterase activity (AChE) was increased by 69% in the cerebral cortex of MAM treated rats, confirming a relative hyperinnervation, whereas in the hippocampus and striatum no significant changes were observed. Despite the marked hyperinnervation, in the cerebral cortex of microencephalic rats neither muscarinic receptor-stimulated phosphoinositide metabolism nor muscarinic receptor density were altered. No differences in receptor density were also observed in the hippocampus and striatum. Chronic diisopropylfluorophosphate (DFP) administration induced a marked decrease of AChE activity and down-regulation of muscarinic receptors whereas atropine administration resulted in receptor up-regulation in cerebral cortex, striatum and hippocampus of both control and MAM rats. The results confirm a relative cholinergic hyperinnervation in the cerebral cortex of microencephalic rats and demonstrate that the regulation of muscarinic receptor-stimulated phosphoinositide metabolism and muscarinic receptor plasticity is not modified in a condition of increased cholinergic presynaptic terminals.

Abnormalities, Drug-Induced↗
PubMed1987

Are there both low- and high-affinity glutamate transporters in rat cortical synaptosomes?

Kinetics of sodium dependent glutamic acid transport have been studied in rat cortical synaptosomes at sufficiently high glutamic acid concentrations ([G]) to delineate the "low affinity" transporter. Computer optimization techniques were used to fit the data to models which account for the sodium and substrate dependence of uptake. The data fit about equally well models consisting of two carriers (Model 1) or one carrier plus a linear component (Model 2). However, the results of further studies were inconsistent with Model 1, but totally consistent with Model 2. Thus the results are incompatible with the presence of both high- and low-affinity carriers. The carrier model found in previous studies of high affinity glutamate transport predicts the effects of high [G] and [Na] observed in the present study. The biphasic effect of [Na] on velocity of uptake is the logical consequence of the operation of this model. The rate equation for this model has been utilized to define and compute kinetic parameters which characterize the transporter. These kinetic functions are remarkably similar in shape and magnitude to previous estimates from the studies of the high affinity transport (low [G]). The results of other studies by the author which corroborate and expand the predictions of the kinetic model are discussed. These have been combined with the present results to formulate a rather comprehensive model of glutamate function. This model can be used to describe function in terms of mathematical equations and to make predictions from these equations. These equations relate velocity of uptake and the kinetic parameters to sodium and substrate concentration, velocity to membrane potential, distribution ratio to the electrochemical potential, and release to time, compartment sizes, and exchange constants. Such processes as concentration in the presynaptic terminal, depolarization induced release, re-uptake following stimulus induced release, and postsynaptic depolarization are all possible consequences of the operation of this model. The wide applicability of the model to the transport of other substrates in addition to glutamate is discussed.

Amino Acid Transport System X-AG↗
PubMed1993

Investigations into the biochemical basis of neuromodulation by 2-phenylethylamine: effect on microtubule protein.

In order to understand the role of 2-phenylethylamine (PE) on neuronal responses, membrane changes have been studied using ESR probes. We report that the anticipated change in lipid membrane fluidity generally implicated in signal transduction has not been observed when PE is added to synaptosomes. As cytoskeletal architecture of presynaptic terminals appears to be involved in synaptic transmission, we non-specifically labeled synaptosomal membrane proteins with the sulfhydryl spin probe N-(2,2,6,6-tetramethyl-piperidine-1-oxyl-4-yl) maleimide (4-MAL-TEMPO). The addition of 2-phenylethylamine was found to induce conformational changes, in decreasing the ratio of weakly to strongly immobilized spin label (W/S) to 65% of the control. Of the membrane proteins labeled, 70-90% of the 4-MAL-TEMPO is covalently incorporated into cytoskeletal proteins. In isolated synaptosomes, incorporated with spin-labeled tubulin, the addition of PE reduced the W/S ratio to 51.6% of that obtained for polymerized microtubules. In vitro, PE reduced tau R of polymerized microtubules by 37%. We propose that the PE interaction with tubulin changes microtubule dynamics which may lead to its neuromodulatory action. The state of microtubular assembly can modulate the responsiveness of second messengers in the cell to the effect of stimulatory agents. The nature and physiological significance of PE interaction with tubulin is currently under investigation.

Animals↗
PubMed1995

Pathologic alterations in pre- and postsynaptic elements in aged mouse sympathetic ganglia.

Dysfunction of the sympathetic autonomic nervous system is an increasingly recognized, although poorly understood, complication of increasing age in experimental animals and man. In this study of young adult (4-6 months old) and aged (12-24 months old) mice we have examined the ultrastructural appearance of perikarya, dendritic processes, preterminal axons, and synapses in selected sympathetic ganglia as well as the three-dimensional structure of the dendritic arborizations of principal sympathetic neurons using intracellular injections of Lucifer Yellow. Ultrastructural examination demonstrated numerous markedly enlarged presynaptic terminal axons and synapses which distorted the contours of perikarya and dendrites of neurons within the prevertebral celiac/superior mesenteric and paravertebral superior cervical and stellate sympathetic ganglia of aged mice. Dilated preterminal axons had the distinctive ultrastructural appearance of neuroaxonal dystrophy, a pathologic process described in a wide variety of clinical and experimental entities. Dystrophic axons were identical in ultrastructural appearance in young and old animals, differing only in frequency. A distinctive type of ultrastructural alteration, characterized by markedly distended neurites containing numerous vacuoles, was confined to the superior cervical ganglia and also increased in frequency with aging. Although many intraganglionic vacuolated processes disappeared with surgical interruption of the cervical sympathetic trunk, which contains the preganglionic axons innervating the superior cervical ganglia, others persisted. In addition, the presence in some processes of admixed ribosomes, lipofuscin, or continuity with the cell body indicated that numerous neuritic alterations within aged sympathetic ganglia were likely of dendritic origin. Intracellular injections of Lucifer Yellow into principal sympathetic neurons demonstrated that the dendritic arborizations of the celiac/superior mesenteric ganglia neurons of young adult mice were significantly more complex and extensive than those of the superior cervical ganglia. Sympathetic neurons of aged superior cervical ganglia, but not superior mesenteric ganglia, appeared significantly smaller with regard to total dendritic length, extent, and branching when compared to those of young animals. In the aged superior cervical ganglia, short, stunted dendritic processes also exhibited large, focal, often multiple, swellings, a phenomenon infrequently observed in the superior cervical ganglia of young animals. The celiac/superior mesenteric ganglia of aged or young adult mouse failed to exhibit comparable dendritic swellings.

Aging↗
PubMed1993

Matching localization of vasoactive intestinal polypeptide (VIP) and VIP-receptor at pre- and postsynaptic sites in the mouse visual cortex.

Vibratome sections of the mouse occipital cortex were processed by double label immunohistochemistry to demonstrate the localization of the receptor for vasoactive intestinal polypeptide and the peptide itself. The receptor was found to be distributed in the cytoplasm and major dendrites of numerous cortical cells, mainly pyramidal neurons. Vasoactive intestinal polypeptide, on the other hand, occurred in a population of non-pyramidal neurons and axonal boutons. Image analysis revealed a close spatial association of peptide-containing presynaptic terminals with receptor-containing cells. Ultrastructurally, these connections represented symmetrical axo-somatic and axo-dendritic synapses. Our findings demonstrate a matching histological localization of vasoactive intestinal polypeptide and its receptor in the brain.

Animals↗
PubMed1992

Immunolocalization of B-50 (GAP-43) in the mouse olfactory bulb: predominant presence in preterminal axons.

Because the growth-associated protein B-50 (GAP-43) has been implicated in neurite outgrowth as well as in synaptic plasticity, we studied its light and electron microscopical distribution in the mouse olfactory bulb, an area of the nervous system which exhibits a high degree of synaptic plasticity. Immunofluorescent staining with monospecific affinity-purified anti-B-50 antibodies revealed that B-50 is most abundantly expressed in the olfactory nerve fibre layer and the granule cell layer neuropil, while little staining was observed in the external plexiform layer and in cell bodies. B-50 is absent from dendrites and myelinated axons as indicated by double labelling with monoclonal antibodies against microtubule-associated protein 2 and the large neurofilament protein, respectively. Using post-embedding immunogold labelling on ultrathin Lowicryl sections, B-50 was found to be highly concentrated in presumed growth cones in the olfactory nerve fibre layer and in thin unmyelinated axons and presynaptic terminals in the granule cell layer neuropil. Near background immunolabelling was seen in perikarya, dendrites and myelinated axons. In view of the implication of B-50 in plasticity-related phenomena, its abundance in the thin unmyelinated preterminal axons suggests that these are potential sites of extrasynaptic plasticity.

Animals↗
PubMed1980

A freeze-fracture study of synaptic junction development in the superficial layers of the chick optic tectum.

Synaptogenesis in the superficial layers of the rostral pole of the chick optic tectum has been studied using freeze-fracture techniques. The developmental sequence of intramembrane organization at synaptic junctions involves the accumulation and assembly of intramembrane particles into aggregates characteristic of the mature junctions. By embryonic day seven, areas of loosely-arranged clusters of medium-sized particles are observed on the cytoplasmic membrane leaflets (P-faces) of developing neurites. These clusters are characteristic of the intramembrane organization at presynaptic active zones. At later stages, small pits, characteristic of vesicle fusion sites, are observed interspersed among such P-face particle clusters. Complementary intramembrane specializations are also present on the external leaflets (E-faces) of presynaptic membranes at the active zones. Small solitary aggregates of large-sized particles on the E-faces of neurite plasma membranes are also seen at early embryonic stages. As development progresses, these aggregates increase in size and packing density and occupy large oval domains in postsynaptic membranes. These intramembrane specializations may represent the postsynaptic active zones of asymmetric synapses. Another type of intramembrane specialization, observed during the third week of incubation, is characterized by aggregates of small- and medium-sized particles on the P-face of postsynaptic membranes and is often seen directly apposed to the E-face of a presynaptic terminal. This type of intramembrane specialization may represent the postsynaptic active zone region at symmetrical synaptic contacts.

Aging↗
PubMed1982

Ultrastructural localization of glycerolipid synthesis in rod cells of the isolated frog retina.

The incorporation of two glycerolipid precursors, 3H-glycerol and 3H-choline, into rod cells of the isolated frog retina has been studied using quantitative electron microscope autoradiography. The results indicate that the endoplasmic reticulum (ER) is the major site of early incorporation of these precursors suggesting that the ER is the primary site of lipid synthesis. Of the different types of ER present in rod cells, the rough ER (RER) and nuclear envelope predominate in this activity. The organized region of smooth ER (SER) in the subellipsoid region does not appear to be of major quantitative importance, although SER closely intermingled with RER in the myoid region may be involved to some extent. We also compared the pattern of labelling observed at various incubation times in 3H-glycerol and 3H-choline with that observed with 3H-leucine. Differences were observed between the pattern of lipid and protein labelling, particularly in the labelling of the Golgi apparatus, mitochondria, plasma membrane, presynaptic terminals and outer segments. This suggests that lipids and proteins may differ in some aspects of the routes and mechanisms by which they are transported from their sites of synthesis to the membrane delimited compartments for which they are destined.

Animals↗
PubMed1982

Ultrastructural studies of young and old mouse neuromuscular junctions.

The ultrastructure of the neuromuscular junction of young and old male CBF-1 mice was analysed both qualitatively and quantitatively. The age-related findings were similar in both the phasic extensor digitorum longus muscle and the tonic soleus muscle but more pronounced in the latter. Presynaptic terminals of old mice compared to young showed decreases in nerve terminal area, mitochondria and synaptic vesicles, but increases in smooth endoplasmic reticulum, coated vesicles, cisternae, microtubules and probably neurofilaments. On the postsynaptic side there were increases in complexity of junctional folds and subsarcolemmal vesicles, and the appearance of lipofuscin deposits. Occasional denervated postsynaptic regions were encountered in old neuromuscular junctions, but the predominant characteristics of aging changes were not those of denervation. Rather, a unique and uniform process involving most of the population of nerve terminals, possibly of physiologically adaptive significance, appears to occur with age in both phasic and tonic limb muscles.

Animals↗
PubMed1996

Chronic levodopa therapy enhances dopa absorption: contribution to wearing-off.

Effects of the chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon are re-evaluated. The concentration of plasma levodopa and clinical symptoms were determined 4 hours after oral levodopa (levodopa 100 mg + benserazide 25 mg) administration on 55 parkinsonian patients. Long-term levodopa therapy markedly increased the peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC); whereas, it decreased time to the peak concentration (Tmax) and the elimination half-life (T1/2). These results suggest that long-term levodopa therapy accelerates the absorption of levodopa. The wearing-off group (n = 23), however, had a markedly higher Cmax and AUC, and a shorter Tmax and T1/2 than the stable group (n = 32). We speculate that the clinical expression of "stable" or "wearing-off" depends on the absorption of levodopa as well as the presynaptic terminal and post synaptic receptors.

Aged↗
PubMed1991

Distribution of synapses on an intracellularly labeled small pyramidal neuron in the cat motor cortex.

The morphological characteristics and distribution of synapses on a small pyramidal neuron in layer III of the cat motor cortex have been studied by combining intracellular HRP staining and electron microscopic examination. The stained neuron showed spiny apical and basal dendritic profiles under the light microscope, and exhibited the morphological features of a pyramidal neuron. Ultrastructural analysis indicated that about 80% of the presynaptic terminals formed asymmetrical synapses with spines of distal apical and basal dendrites. On proximal apical dendrites, 64% of the synapses were found to make contact with spines, and 16.7% of the synapses were of symmetrical type and formed with dendritic shafts. Two types of terminal could be identified on the soma; they were alternately located and established symmetrical and asymmetrical synaptic contacts respectively. Possible functional implications are discussed.

Animals↗
PubMed1979

A note on the mechanism of action of UV-irradiation of amphibian embryos.

The actions on amphibian embryos of UV-irradiation, exposure to Li+ or exposure to ouabain show interesting parallels with their effects on spontaneous release at the presynaptic terminals of the neuromuscular junction. It is suggested that these treatments serve to raise intracellular Ca2+ ([Ca2+]i) in these examples, and that UV-promoted abnormalities in embryogenesis are a consequence of changes in [Ca2+]i at critical stages in development.

Amphibians↗
PubMed1994

Long-term potentiation in the piriform cortex is blocked by lead.

1. Long-term potentiation (LTP) is a prolonged increase in synaptic efficacy that is triggered by a brief tetanic stimulation at certain central synapses. LTP is one of the best available model systems available to the neurophysiologist of neuronal plasticity such as that underlying learning and memory. 2. We have studied the susceptibility of LTP to blockade by lead as a test of the hypothesis that the negative effect of lead on intelligence in children may result from interference with this process. LTP was studied in slices of rat piriform cortex. At this site, as in many other central synapses, LTP requires activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors, and we investigated whether lead actions, if any, were mediated via effects on NMDA-activation ion channels or, alternatively, at voltage-activated calcium channels. 3. We find that lead blocks LTP at low micromolar concentrations. However, concentrations of lead that totally block LTP had no apparent effect on either NMDA-activated responses or presynaptic calcium channels, as monitored by transmitter release from presynaptic terminals. 4. While the mechanism of lead blockade of LTP remains to be determined, these observations are consistent with the hypothesis that the cognitive effects of lead neurotoxicity may result from effects on LTP.

2-Amino-5-phosphonovalerate↗
PubMed1994

The disruptive effects of ketamine on passive avoidance learning in mice: involvement of dopaminergic mechanism.

The involvement of dopaminergic mechanisms in ketamine-induced disruption of one trial step-through passive avoidance performance was assessed through the coadministration with the dopamine D1 antagonist SCH 23390, the dopamine D2 antagonist YM-091512 and the dopamine autoreceptor agonist at low doses, apomorphine, in mice. Pretraining (10 min before) administration of ketamine (0; saline, 2.5, 5 and 10 mg/kg SC) dose-dependently reduced the latency in the retention trial conducted 24 h after the training. However, ketamine did not affect the retention latency when administered immediately after the training or prior to retention. YM-09151-2 (0.01 and 0.03 mg/kg SC) and apomorphine (0.01 and 0.03 mg/kg SC), but not SCH 23390 (0.01 and 0.03 mg/kg SC), ameliorated the impaired reduction by ketamine (10 mg/kg) in a dose-dependent manner. These results suggest that ketamine obstructs the acquisition of the passive avoidance task, and that this effect is induced by stimulation of dopamine D2 receptors through dopamine release from the presynaptic terminals.

Animals↗