Synaptic Transmission between Neurons

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8 Synaptic Transmission between Neurons

Chapter Outline

Synaptic Strength Can Be Facilitated or Depressed

Messages Also Travel across Synapses in a Retrograde Direction

Most Neurotransmitters Are Small Amine Molecules, Amino Acids, or Neuropeptides

Gap Junctions Mediate Direct Current Flow from One Neuron to Another

In contrast to the way in which information travels within individual neurons as electrical signals, information is usually transmitted between neurons through the release of neurotransmitters at specialized junctions called synapses. And in contrast to unvarying, always depolarizing action potentials, a wide variety of slow graded potentials may be produced at the synapses on an individual neuron—some depolarizing, some hyperpolarizing, some milliseconds in duration, others seconds, minutes, or even hours.

There Are Five Steps in Conventional Chemical Synaptic Transmission

The fundamental elements of a chemical synapse (Fig. 8-1) are a presynaptic ending from which neurotransmitter is released, a synaptic cleft across which it diffuses, and a postsynaptic element containing receptor molecules to which the neurotransmitter binds. Although the presynaptic ending is usually an axon terminal and the postsynaptic ending usually a dendrite, any part of a neuron can be presynaptic to any part of another neuron. The essential processes at chemical synapses are presynaptic synthesis, packaging, and release of neurotransmitter; binding to postsynaptic receptors; and termination of neurotransmitter action.

Figure 8-1 Cartoon of a typical chemical synapse.

Neurotransmitters Are Synthesized in Presynaptic Endings and in Neuronal Cell Bodies

As described a little later, most neurotransmitters are either small molecules (e.g., amino acids) or peptides. Small-molecule transmitters are synthesized in presynaptic cytoplasm by soluble enzymes that arrived there by slow axonal transport. Peptide transmitters are synthesized in the cell body, loaded into vesicles, and shipped to presynaptic endings by fast axonal transport.

Neurotransmitters Are Packaged into Synaptic Vesicles before Release

Neurotransmitters are packaged for release from presynaptic endings in collections of synaptic vesicles (THB6 Figure 8-5, p. 181). All presynaptic endings contain a complement of small vesicles, with specific transporters in their walls that pack them full of small-molecule transmitters. Many also contain some less numerous large vesicles containing peptides shipped from the cell body; one or more small-molecule transmitters are often added to the brew in these large vesicles. Small vesicles are located near the presynaptic membrane, whereas large vesicles are usually located farther away.

Presynaptic Endings Release Neurotransmitters into the Synaptic Cleft

Neurotransmitter release is a secretory process triggered by an increase in presynaptic Ca²⁺ concentration. The membranes of presynaptic terminals contain voltage-gated Ca²⁺ channels that open when an action potential spreads into the terminal (Fig. 8-2). Ca²⁺ influx causes one or more vesicles to fuse with the presynaptic membrane and dump its neurotransmitter content into the synaptic cleft. Because small vesicles are close to the synaptic cleft, they are the first to release their contents. Because the large vesicles are farther away, release of their contents requires more Ca²⁺ entry (hence, more presynaptic action potentials) and more time.

Figure 8-2 Calcium-stimulated release of neurotransmitter.

Neurotransmitters Diffuse Across the Synaptic Cleft and Bind to Postsynaptic Receptors

The effects of neurotransmitters are mediated by receptors situated in or near postsynaptic membranes. Receptors for the transmitters in small vesicles are mostly located right across the synaptic cleft, contributing to the rapid action of these transmitters. Receptors for peptides are often located outside the synaptic cleft, contributing to the slowness of large-vesicle effects.

Neurotransmitter Action Is Terminated by Uptake, Degradation, or Diffusion

A concerted effort is made to remove neurotransmitter soon after it is released so that the postsynaptic element will be prepared for subsequent releases. Several different mechanisms are used, with different kinds of synapses emphasizing different mechanisms. Most commonly, transmitter is taken back up by the presynaptic ending or by nearby glial cells, but some transmitters are degraded by enzymes in the synaptic cleft or simply diffuse away.

Synaptic Transmission Can Be Rapid and Point-to-Point, or Slow and Often Diffuse

Postsynaptic responses to transmitter binding can be either depolarizing or hyperpolarizing. Because depolarizing and hyperpolarizing events move the postsynaptic membrane closer to or farther from threshold, they are referred to respectively as excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). Depending on the synapse and the transmitter, both EPSPs and IPSPs can be either fast (lasting a few milliseconds) or slow.

Rapid Synaptic Transmission Involves Transmitter-Gated Ion Channels

Fast EPSPs and IPSPs are produced by the binding of neurotransmitter to a receptor that is itself a ligand-gated ion channel (Fig. 8-3); because of the direct coupling to ion flow, these are also referred to as ionotropic receptors. The permeability change induced by the binding of transmitter determines the postsynaptic response. Some receptors become permeable to both Na⁺ and K⁺, causing depolarization (EPSP). Others become permeable to K⁺ or Cl⁻, causing hyperpolarization (IPSP).

Figure 8-3 Fast postsynaptic potentials, mediated by binding of small-molecule transmitters to ligand-gated ion channels.

Slow Synaptic Transmission Usually Involves Postsynaptic Receptors Linked to G Proteins

Slow EPSPs and IPSPs are produced by a multistep process involving changes in the postsynaptic concentration of a second messenger. They typically begin with binding of neurotransmitter to a receptor linked to an adjacent guanine nucleotide-binding protein (G protein). The G protein then dissociates and one of its subunits triggers subsequent steps. In the simplest case, the G protein subunit is itself the second messenger and binds to a ligand-gated ion channel (Fig. 8-4). In most cases, however, the G protein subunit increases or decreases the activity of an enzyme, which in turn causes changes in the concentration of something else. Because of the intermediate metabolic steps, the receptors involved in slow EPSPs and IPSPs are also referred to as metabotropic receptors.

Figure 8-4 Slow postsynaptic potentials, usually mediated by binding of small-molecule transmitters or peptides to G protein-coupled receptors and subsequent dissociation of G proteins. G protein subunits (G) can have a variety of effects. They can be as simple as the indicated opening of a channel but are usually more complex, involving activation of an enzyme or even alteration of gene expression.

The Postsynaptic Receptor Determines the Effect of a Neurotransmitter

Although some neurotransmitters usually have either excitatory or inhibitory effects, the nature of the postsynaptic response to a transmitter is actually determined by the postsynaptic receptor. Hence, a given neurotransmitter can produce EPSPs at some synapses and IPSPs at others, or slow postsynaptic potentials at some synapses and fast ones at others. For example, acetylcholine, the first neurotransmitter discovered, produces fast EPSPs at neuromuscular junctions (by binding to nicotinic receptors there) and slow EPSPs or IPSPs at other synapses (by binding to muscarinic receptors).

The Size and Location of a Synaptic Ending Influences the Magnitude of Its Effects

All chemical synapses have the basic elements just described, but nevertheless come in a variety of configurations with different functional characteristics. Most CNS presynaptic endings, for example, are tiny, contain vesicles clustered for release at just one or a few active zones, and produce very small postsynaptic potentials in response to a presynaptic action potential. Neuromuscular endings and a few specialized CNS presynaptic endings, in contrast, contain many active zones and produce large postsynaptic potentials in response to a presynaptic action potential (THB6 Figure 8-13, p. 187). The proximity of a synapse to the trigger zone for action potential production also has important implications for the effects of transmitter release. Postsynaptic potentials initiated far out on a dendrite will largely die out as they spread passively toward the trigger zone, whereas those initiated near the trigger zone will reach it with little decrement.

Presynaptic Endings Can Themselves Be Postsynaptic

The synapses mentioned so far have effects on the entire postsynaptic neuron, increasing or decreasing the likelihood that it will fire. Another, more selective, kind of synapse is one in which a presynaptic terminal receives synaptic inputs from other axon terminals, suppressing or facilitating Ca²⁺ entry into the terminal. The resulting presynaptic inhibition or presynaptic facilitation is a clever mechanism for selectively affecting only selected outputs from one neuron to another (THB6 Figure 8-15, p. 188).

Synaptic Strength Can Be Facilitated or Depressed

The amount of transmitter released by a presynaptic terminal in response to an action potential invading it is not constant, but rather depends on the history of activity in that terminal. There are several short-lived processes that result in the release of more or fewer vesicles (potentiation and depression, respectively). Other processes lasting for days or longer involve insertion or removal of postsynaptic receptors. The resulting long-term potentiation or long-term depression is thought to play a fundamental role in learning and memory.

Messages Also Travel Across Synapses in a Retrograde Direction

The synaptic transmission described so far is the mechanism used to convert electrical activity in one neuron into electrical activity in other neurons. However, there is also chemical signaling in the opposite direction that is electrically silent and does not depend on synaptic vesicles. Membrane-derived endocannabinoids, gases such as nitric oxide and carbon monoxide, and larger molecules that serve as growth factors can all be released by postsynaptic neurons and have effects on presynaptic endings or neurons.

Most Neurotransmitters Are Small Amine Molecules, Amino Acids, or Neuropeptides

Key Concepts

Acetylcholine mediates rapid, point-to-point transmission in the PNS.

Amino acids mediate rapid, point-to-point transmission in the CNS.

Amines and neuropeptides mediate slow, diffuse transmission.

Nearly all neurotransmitters are either small molecules (amines or amino acids) or neuropeptides. There are dozens of known or suspected neuropeptide transmitters, but a much smaller number of important small-molecule transmitters, each with a more or less distinctive role (Tables 8-1 and 8-2). Acetylcholine mediates rapid, point-to-point, excitatory transmission in the PNS. Glutamate and γ-aminobutyric acid (GABA) mediate rapid excitatory and inhibitory transmission, respectively, in the CNS. Amines and neuropeptides almost without exception mediate slow, second-messenger effects in the CNS and PNS.

Table 8-1 Principal small-molecule transmitters

Amines

Acetylcholine

Monoamines

Serotonin

Catecholamines

Dopamine

Norepinephrine

Amino acids

Glutamate

GABA (γ-aminobutyric acid)

Table 8-2 Structures, locations, and actions of the principal small-molecule transmitters

Transmitter	Principal Neurons Using It	Major Action*
Acetylcholine

Lower motor neurons Fast excitatory Preganglionic autonomics Various Postganglionic parasympathetics Second messenger Basal nucleus (Chapter 11) Second messenger Other CNS sites Second messenger Glutamate

Primary sensory neurons Fast excitatory^† Many CNS interneurons Fast excitatory^† Many CNS projection neurons Fast excitatory^† γ-aminobutyric acid (GABA)