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Neurosciences Research: Volume 4

Neurosciences Research: Volume 4

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Neurosciences Research: Volume 4

553 Seiten
5 Stunden
Oct 22, 2013


Neuroscience Research, Volume 4 covers papers on a varied group of studies, ranging from synaptic transmission and local anesthetic action to the immobility reflex ("animal hypnosis") and control of food intake. The book presents papers on the mechanisms of synaptic transmission; the acetylcholine system and neural development; and the site of action and active form of local anesthetics. The text also includes papers on biological rhythms and their control in neurobehavioral perspective; neurophysiologic studies of the immobility reflex ("animal hypnosis" and the hepatic receptors and the neurophysiological mechanisms controlling feeding behavior. Neuroscientists, physiologists, and psychiatrists will find the book useful.
Oct 22, 2013

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Publisher Summary

Generally, the mechanisms of synaptic transmission can be divided into three types of transmission. At most junctions, the synaptic transmitter has been found to increase the permeability of the postsynaptic membrane to certain ions. At a few junctions, however, particularly in invertebrates and in lower vertebrates, transmission is not chemically mediated but is clearly electrical. Recently, a third type of transmission mechanism has been recognized, namely, chemical transmission that activates metabolic systems in the postsynaptic neuron without increasing the ion permeability of the postsynaptic membrane. The chapter discusses the various mechanisms of synaptic transmission. It illustrates the basic mechanisms of synaptic transmission by discussing those junctions where the mechanism of transmission has been most clearly elucidated. Communication between nerve cells—synaptic transmission—may be accomplished in several different ways. There may be direct electrical coupling between neural elements that transmit information in either direction or in one direction only. Alternatively, a chemical transmitter may be released presynaptically that may increase the postsynaptic ion permeability or may activate metabolic systems requiring cellular energy. The recent reports show that late, slow synaptic potentials increase the duration of synaptic action manifold but the durations of these synaptic potentials are still only in the range of seconds and, thus, do not bridge the gap to the long-term changes of memory. Nevertheless, the possibility that a synaptic transmitter may be able to activate metabolic systems of a nerve cell may provide a fruitful field for the future investigation of possible long-term changes resulting from synaptic activity.

I. Introduction

II. Chemical Transmission: Ion Permeability Mechanisms

A. Excitatory Junctions

B. Inhibitory Junctions

III. Electrical Transmission

A. Bidirectional Electrical Transmission

B. Unidirectional Electrical Transmission

C. Electrical Inhibition

D. Combined Electrical and Chemical Transmission

IV. Chemical Transmission: Activation of Metabolic Systems

A. Synaptic Inactivation of Potassium Conductance

B. Synaptic Activation of Electrogenic Sodium Pump

C. Norepinephrine Activation of Cyclic AMP

V. General Conclusions


I Introduction

The junctional region between two nerve cells was designated a synapse by Sherrington. Early experimental investigation of peripheral synapses showed that the vagus inhibits the heart by release of a chemical transmitter, with properties similar to acetylcholine (Loewi, 1921), and sympathetic stimulation releases an epinephrine-like substance that accelerates the heart (Cannon and Bacq, 1931). Subsequent investigation on the peripheral nervous system established that acetylcholine is the synaptic transmitter at the neuromuscular junction (Dale et al., 1936) and in sympathetic ganglia (Feldberg and Gaddum, 1934), while norepinephrine is the transmitter for postganglionic sympathetic neurons (von Euler, 1948). There ensued a controversy over whether synaptic transmission in the central nervous system (CNS) is chemical or electrical (cf. Feldberg, 1945; Eccles, 1949). Subsequently, intracellular recording from central neurons has revealed that the synapses studied in the mammalian CNS appear to have the changes associated with chemical transmission (cf. Eccles, 1964), although the chemical transmitter at most central junctions is unknown.

The mechanisms of synaptic transmission have been extensively investigated during the past 20 years and in general can be divided into three types of transmission. At most junctions, the synaptic transmitter has been found to increase the permeability of the postsynaptic membrane to certain ions. At a few junctions, however, particularly in invertebrates and in lower vertebrates, transmission is not chemically mediated, but is clearly electrical. Recently, a third type of transmission mechanism has been recognized—the synaptic activation of metabolic systems. In order to understand this recent advance more fully, the various mechanisms of synaptic transmission will be reviewed. The basic mechanisms of synaptic transmission will be illustrated by discussing those junctions where the mechanism of transmission has been most clearly elucidated. For more detailed reviews of the older literature, the reader is referred to McLennan (1963) and Eccles (1964).

II Chemical Transmission: Ion Permeability Mechanisms


The neuromuscular junction has been studied in great detail, and much information obtained there is relevant to our understanding of chemical transmission in the nervous system. Excitation of the terminal portions of motor nerve fibers releases acetylcholine from the terminals. The mechanisms of release have been studied extensively in recent years, and it is known that the release occurs in a stepwise or quanta! fashion (Fatt and Katz, 1952; del Castillo and Katz, 1954b), and that calcium is necessary for the release (del Castillo and Stark, 1952), while excess magnesium inhibits it (del Castillo and Engbaek, 1954; del Castillo and Katz, 1954a). Since transmitter release has recently been reviewed (Katz, 1969), we will focus on postsynaptic aspects of synaptic transmission.

If a recording microelectrode is inserted intracellularly in a frog muscle fiber, the resting membrane potential is about 90 mV negative with respect to the surrounding Ringer’s bath. At the end-plate region of the muscle, the electric response following stimulation of motor nerves is a depolarization (a reduction in membrane potential), termed the end-plate potential (EPP). The EPP begins after a synaptic delay of approximately 0.6–1.0 msec and, in curarized muscle, consists of a single monophasic wave (Fig. 1A) that reaches its peak amplitude in a little more than 1 msec and declines to one half in another 2 msec (Fatt and Katz, 1951). The mechanism by which the synaptic transmitter, acetylcholine, produces this change in potential at the end-plate membrane has been investigated by several techniques.

FIG. 1 (A) Diagram of end-plate potential in curarized muscle. Ordinate: depolarization of membrane potential from resting potential in mV. Abscissa: time from onset of EPP in msec. (B) Diagram of end-plate current, indicating time course of current flow responsible for end-plate potential.

The current flow responsible for the EPP has been measured directly using the voltage clamp technique (Takeuchi and Takeuchi, 1959). In this technique, the membrane potential is maintained at resting potential by a feedback circuit. The feedback current necessary to hold the membrane potential at the resting level during neuromuscular transmission provides a measure of the end-plate current during the active phase of the EPP. Such experiments show the end-plate current rises rapidly to a peak in about 0.7 msec and then falls approximately exponentially to one half in another 1.08 msec (Fig. 1B). The total duration of the end-plate current measured by this method is about 4–5 msec. It is clear that the EPP has a much longer duration than the end-plate current (Fig. 1). After the brief initial phase of current flow across the end-plate membrane, the slow decline of the EPP is attributed to the passive dissipation of electric charge along and across the muscle membrane and is determined by the cable constants of the muscle fiber (Fatt and Katz, 1951; Boyd and Martin, 1956).

The alteration in the end-plate membrane that accounts for the end-plate current has been studied by determining the membrane resistance during the EPP. When a rectangular current pulse is passed across the membrane, the resulting change in membrane potential is a function of the membrane resistance. The specific membrane resistance (Rm) of frog sartorius muscle is on the order of 4000 ohm-cm² (Fatt and Katz, 1951). During the active phase of the end-plate potential, there is a tremendous reduction in the resistance of the end-plate membrane to about 40 ohm-cm² or about 1% of the resting value (Fatt and Katz, 1951). Since electric conductance is defined as the reciprocal of resistance, we can say that during the action of transmitter there is a large increase in the postsynaptic membrane conductance. In the fluid medium of a cell, the electric current of this conductance will be carried by the movement of ions; thus the conductance may be taken as an index of ion permeability.

Since the movement of an ion across the membrane is determined by the membrane permeability to that ion, the electric potential across the membrane, and the concentration difference of the ion across the membrane, it is possible to study the ionic mechanisms of the synaptic potential by changing the potential gradient across the membrane and by altering the ionic composition either extracellularly or intracellularly.

The membrane potential can be changed over a wide range by passing electric currents through an intracellular electrode. When the muscle fiber is hyperpolarized, the size of the EPP is increased, while depolarization reduces the size of the EPP. The relationship between membrane potential and EPP is approximately linear (Fatt and Katz, 1951). The EPP is zero at a membrane potential of about –15 mV, which is the equilibrium potential for the ionic current underlying the EPP (del Castillo and Katz, 1954c). When membrane potential is displaced above that level, the EPP is reversed. The equilibrium potential for individual ions can be calculated from the Nernst equation (cf. Katz, 1966); for example, the equation for calculating the equilibrium potential of sodium (ENa) is

where R, T, and F have their usual meanings of gas constant, absolute temperature, and the Faraday and Nao and Nai are the external and internal concentration of sodium. The sodium equilibrium potential may thus be calculated to be approximately +50 mV, differing significantly from the equilibrium potential of the EPP. The equilibrium potentials for potassium and chloride, on the other hand, are near the resting membrane potential, or about –90 mV. Thus, the equilibrium potential of the EPP does not correspond to the equilibrium potential of the three prevalent inorganic ions but may be explained by some combination of these conductances.

The question of the ion conductances involved in the EPP has been studied by changing the ionic composition of the external bathing solution and determining the effect on the end-plate current (Takeuchi and Takeuchi, 1960). Reduction in external Na concentration shifts the equilibrium potential for the end-plate current in the hyperpolarizing direction. The equilibrium potential of the end-plate current also shifts in the hyperpolarizing direction when the concentration of K is reduced. Removal of Cl, however, does not appreciably alter the equilibrium potential of the end-plate current. These results indicate that the transmitter, ACh, increases the permeability of the end-plate membrane to Na and K but produces little or no change in Cl permeability.

The puffer fish poison, tetrodotoxin, specifically blocks the regenerative increase in Na conductance associated with nerve and muscle action potentials (cf. Kao, 1966), but does not affect the postsynaptic Na conductance associated with the EPP (Katz and Miledi, 1967), demonstrating that the Na conductance of electric excitation in nerve or muscle is different from the Na conductance associated with chemical junctional transmission.

In summary, the synaptic transmitter at the neuromuscular junction interacts with receptors in the postsynaptic membrane altering the properties of the membrane so that it becomes highly permeable to the small cations Na and K. These permeabilities may be represented in an equivalent electrical circuit (Fig. 2) by conductances to sodium (gNa) and potassium (gK). The conductances are switched on together by ACh activation of postsynaptic receptors. The equilibrium potentials for sodium and potassium are electromotive forces, ENa and EK, respectively, in series with the conductance channels. The current carried by each ion through the membrane will be the product of the conductance and the difference between the membrane potential and the equilibrium potential for that ion. The equation for a synaptic current (Is) involving a sodium conductance (gNa) and a potassium conductance (gK) is

FIG. 2 Equivalent electric circuit diagram for end-plate potential. On the right are synaptically activated (coupled switches) conductances to sodium (gNa) and potassium (gK) in series with their equilibrium potentials (represented as emf’s), ENa and EK. On the left is diagramed the nonsynaptic membrane with the membrane resistance, Rm, in series with the electromotive force, Em, and in parallel with the membrane capacitance, Cm. R1 is the longitudinal membrane resistance.

Thus, with the synaptically activated increase in the postsynaptic membrane permeability, ions move passively across the membrane in relation to their electrochemical gradients to generate the EPP. We will now consider other examples of such synaptic conductance mechanisms.

In sympathetic ganglion cells, stimulation of the preganglionic nerve leads to the generation of a fast excitatory postsynaptic potential (EPSP) that has been well studied. Acetylcholine released from preganglionic nerve terminals generates the fast EPSP by its action on nicotinic receptors (Eccles, 1955; Blackmail et al., 1963). The EPSP has a synaptic delay of approximately 1.5 or 2.5 msec (depending on the postganglionic cell), reaches its maximum amplitude in about 2.5–3 msec, and has a duration of approximately 40 msec (Eccles, 1955; Nishi and Koketsu, 1960).

When the effect of the EPSP on membrane resistance is tested by passing rectangular constant current pulses across the membrane, the EPSP is associated with a marked reduction in the membrane resistance (Kobayshi and Libet, 1968). Electric polarization of the membrane over a wide range reveals an approximately linear relationship between the size of the EPSP and the membrane potential; the equilibrium potential for the EPSP being approximately –10 to –20 mV (Nishi and Koketsu, 1960). When chloride is removed from the bathing solution, the equilibrium potential is not altered. Decreasing the external Na concentration shifts the equilibrium potential toward the resting membrane potential, as does decreasing the external K. Increasing the external K shifts the equilibrium potential toward zero (Koketsu, 1969). These results indicate that the EPSP is produced by an increased conductance of the postsynaptic membrane to Na and K.

We may conclude that although there are some differences between this EPSP in sympathetic ganglion cells and the EPP at the neuromuscular junction, such as synaptic delay and time course of the postsynaptic excitatory potential, the basic mechanism of generation of these excitatory synaptic potentials appears to be similar. (There may be some quantitative differences in the Na and K conductances involved, but in both cases an increased conductance to these ions generates the excitatory synaptic potential.)

In the mammalian CNS, the mechanisms of synaptic transmission have been studied most extensively on spinal motoneurons (cf. Eccles, 1957, 1964). Electrical stimulation of Ia afferent fibers generates an EPSP in functionally similar motoneurons after a synaptic delay of about 0.3 msec. The Ia EPSP reaches its summit in about 1.2 msec and decays more slowly with an approximately exponential time course, having a time constant of approximately 4.0 msec. Increasing the stimulus strength to Ia afferents increases the size of the EPSP (by activating increasing numbers of Ia fibers) until a maximal Ia volley is reached.

Although the transmitter has not yet been identified, the Ia EPSP is presumed to be a chemically mediated synaptic potential. When the motoneuron is depolarized by passing a steady current through an intracellular electrode, the Ia EPSP usually decreases in size with progressive depolarization (Coombs et al., 1955b), as does the EPP at the neuromuscular junction. When the motoneuron is progressively hyperpolarized, however, there is little increase in the size of the EPSP (Coombs et al., 1955b; Nelson and Frank, 1967). This deviation in behavior from that expected for a chemical conductance change has recently been explained by the demonstration (Nelson and Frank, 1967) that in many motoneurons, membrane resistance is decreased when the membrane is hyperpolarized (anomalous rectification). In a few motoneurons, the equilibrium potential of the EPSP has been found to be approximately 0 mV (Coombs et al., 1955b); in others, however, there is no clear-cut reversal potential for the EPSP or only a late phase of the PSP is reversed (Smith et al., 1967). Since it is not possible to change the extracellular ion composition over a wide range for cat motoneurons, ions have been injected intracellularly; however, these injections fail to produce any significant change in the EPSP (Coombs et al., 1955b). Furthermore, when an attempt is made to measure a resistance (impedance) change accompanying the EPSP, less than half of the EPSPs are associated with a detectable decrease in membrane resistance, and that change is often small (Smith et al., 1967). These deviations in behavior from what would be expected on the basis of an ionic conductance mechanism responsible for the generation of the EPSP have recently been explained by the proposal that the Ia synaptic input is widely distributed over the surface of the motoneuron so that a significant fraction of the conductance change underlying the EPSP occurs on the dendrites some distance away from the soma (Smith et al., 1967; Rall et al., 1967). Despite these complexities, it is generally believed that the Ia EPSP is due to the action of a chemical transmitter increasing the ionic conductance of the postsynaptic membrane. The analysis of synaptic potentials in central neurons, however, may be complicated by spatial distribution of synapses on dendritic branches.

As discussed above, synaptic excitation of the neuromuscular junction and sympathetic ganglion cells involves similar basic mechanisms, namely an increased permeability of the postsynaptic membrane to Na and K. It should be noted, however, that in general synaptic excitation does not necessarily involve an increased Na and K conductance. For example, in some molluscan neurons cholinergic excitation is produced by an increased permeability of the membrane to Cl ions, with a net efflux of this anion depolarizing the cell (Frank and Tauc, 1964; Oomura et al., 1965; Chiarandini et al., 1967). In these neurons, an increase in Cl conductance producing a depolarization has been explained by assuming an inward Cl pump that increases the intracellular Cl relative to the extracellular fluid. In other cells, ACh depolarizes by increasing the permeability to Na ions (Chiarandini et al., 1967). These examples illustrate that although the specific ions involved may differ, synaptic excitation at most synapses appears to have a similar basic mechanism—the synaptic transmitter increases the postsynaptic permeability to ions resulting in a net inward flow of current through the subsynaptic membrane. The membrane potential is shifted toward the equilibrium potential of the ions involved, depolarizing the membrane and bringing the potential toward or above threshold for generating action potentials.


In addition to excitation, another important aspect of synaptic transmission is inhibition. We will now consider the mechanisms involved in generating postsynaptic inhibition.

The mechanism of postsynaptic inhibition in the mammalian CNS has been most extensively investigated in cat motoneurons (cf. Eccles, 1957, 1964). The inhibitory synaptic action produced by stimulation of Ia afferents and recorded intracellularly in antagonist motoneurons is a hyperpolarization of the membrane. The time course of the Ia IPSP (Fig. 3A) is similar to the Ia EPSP except that the time constant of decay is closer to the membrane time constant. The postsynaptic inhibitory current (Fig. 3B) measured by voltage clamping the motoneuron, has a rapid time course reaching a peak in about 0.8 msec and having a duration of about 2.5 msec (Araki and Terzuolo, 1962); the falling phase, however, may be prolonged depending on the spatial distribution of inhibitory synapses on the dendrites. In contrast to the observations on Ia EPSPs, there is a demonstrable change in membrane resistance associated with all the IPSPs studied (Smith et al., 1967).

FIG. 3 (A) Diagram of inhibitory postsynaptic potential in motoneuron. Ordinate: hyperpolarization of membrane from resting potential in mV. Abscissa: time from onset of IPSP in msec. (B) Inhibitory postsynaptic current, indicating time course of current flow responsible for

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