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Synaptic physiology I
Objectives
- 1.
Describe the structure and function of electrical synapses.
- 2.
Describe the structure of a representative chemical synapse.
- 3.
Explain the quantal nature of neurotransmitter release.
- 4.
Describe the mechanism of transmitter release and the role of calcium.
- 5.
Describe the synaptic vesicle cycle.
- 6.
List the mechanisms that underlie short-term synaptic plasticity.
The synapse is a junction between cells that is specialized for cell-cell signaling
In Section II, we learned how the action potential (AP) is generated and conducted in neurons and muscle cells. The critical issue in the nervous system is to get the right signal to the right place in the body at the right time. A key question then is, “How is the signal communicated from cell to cell, that is, from neuron to neuron, or from neuron to neuroeffector (muscle or gland) cell?” The intercellular junction through which the signals are transmitted is called the synapse , a
Charles Sherrington, the physiologist who coined the term synapse in the late 19th century, was a recipient of the 1932 Nobel Prize in Physiology or Medicine for his seminal work on spinal reflexes.
and the communication across this junction is therefore called synaptic transmission. In this section (Chapters 12 and 13 ), we elucidate the cellular and molecular mechanisms that underlie synaptic transmission.
Approximately 100 billion neurons are present in the human brain. Moreover, neurons branch like trees, and the average neuron has approximately 1000 branches, each ending in a small swelling, the presynaptic portion of the synapse, which is known as the presynaptic terminal or synaptic bouton . Thus the human nervous system has on the order of 100 trillion (10 14 ) synapses! Adding to the complexity is the fact that most neurons receive inputs from multiple neurons. The average neuron receives many more than 1000 synaptic inputs; indeed, a cerebellar Purkinje neuron may receive as many as 200,000! These neurons and synapses play essential roles in an enormous number of bodily activities from the control of respiration, blood circulation, and renal and gastrointestinal function to sensory perception, body movements, and learning and memory. Our task here is to understand the mechanisms by which neurons communicate with one another.
Synaptic transmission can be either electrical or chemical
In the 19th century, the classic morphological studies of Santiago Ramón y Cajal demonstrated that the nervous system, like other organs, is composed of cells (the neuron doctrine ). b
Cajal and Camillo Golgi shared the 1906 Nobel Prize in Physiology or Medicine for their seminal work on neuronal structure. Ironically, Golgi, whose staining methods proved crucial for elucidating neuronal structure, favored the idea that the nervous system was a continuous reticulum rather than a network of discrete cells.
During the late 19th and early 20th centuries there was fierce debate over two divergent views of synaptic transmission, dubbed the “war of soups and sparks.” a
Valenstein ES: The war of the soups and the sparks: the discovery of neurotransmitters and the dispute over how nerves communicate, New York, 2005, Columbia University Press.
As a result of the demonstration that nerves and muscle cells conduct electrical signals, one popular idea was that an electric “spark” at the end of a presynaptic neuron directly triggered the electrical signal in the postsynaptic neuron or muscle cell (i.e., synaptic transmission was thought to be purely electrical). Conversely, studies on the paralytic action of curare , b
Curare, or D-tubocurarine, is an alkaloid toxin from the bark of a South American liana vine.
and on the autonomic nervous system , hinted at the idea of chemical transmission.
The discovery of chemical synaptic transmission, and recognition that most synapses are chemical, nearly led to the demise of the concept of electrical transmission. Nevertheless, some synapses in the mammalian central nervous system (CNS) are electrical. We will consider the mechanism of transmission at electrical synapses before turning to the more prevalent and diverse chemical synapses.
Electrical synapses are designed for rapid, synchronous transmission
Chemical and electrical synapses have distinct morphological features that are related to their differing functional properties. Electrical synapses are designed to allow current to flow directly from one neuron to another. At electrical synapses, the presynaptic and postsynaptic membranes are separated by only 3 to 4 nm ( Fig. 12.1 A). At these narrow gaps the two neurons are connected by gap junction channels, each of which consists of two hemichannels: one in the presynaptic and one in the postsynaptic membrane. Each hemichannel, called a connexon , is an annular assembly of six polypeptide subunits, called connexins . The connexon in the presynaptic membrane docks face-to-face with a connexon in the postsynaptic membrane to form a conducting channel that connects the cytoplasm of the two neurons ( Fig. 12.1 B). Gap junction channels allow the passage of nutrients, metabolites, ions, and other small molecules (≤1000 daltons). More than 20 connexin isoforms have been identified, and mutations in about half of the genes that encode these proteins are linked to human disease ( Box 12.1 ).
BOX 12.1
Connexin Mutations Linked to Disease
Mutations in about half of the genes that encode the connexin family of proteins have been linked to several diseases. In some of these diseases, the connexin mutations result in dysfunctional gap junctions between glial cells. Mutations in the gene encoding connexin-32 (Cx32), for example, are associated with the X-linked form of Charcot-Marie-Tooth disease, one of the most common hereditary neurological disorders. Charcot-Marie-Tooth disease is a motor and sensory neuropathy characterized by muscle weakness and various sensory defects. Many of the Cx32 mutants fail to form functional gap junctions between Schwann cells, and this leads to demyelination and axonal degeneration. Recessive mutations in the gene encoding connexin-47 (Cx47) are linked to Pelizaeus-Merzbacher–like disease, a rare disorder characterized by lack of CNS myelin development. The Cx47 mutants also fail to form functional gap junction channels. Mutations in Cx26 are implicated in deafness. This connexin is normally expressed in the nonsensory epithelial cells in the cochlea, and not in the hair cells. The exact function of Cx26 in the cochlea is unknown, but it has been proposed to play a role in the recycling of K + .
In the majority of connexin mutants that have been studied, the altered connexin subunits reach the cell surface and form gap junction-like structures. However, these structures either are nonfunctional or they form channels that function poorly compared with normal gap junction channels. In another class of mutants, the altered connexin subunits are retained in the endoplasmic reticulum and never reach the cell surface.
The first description of electrical synaptic transmission was based on studies of the crayfish giant motor synapse. In this preparation, the presynaptic and postsynaptic axons are large enough to allow placement of intracellular stimulating and recording electrodes close to the synapse. These experiments demonstrated that an AP in the presynaptic neuron produces a depolarization in the postsynaptic neuron after a negligible synaptic delay ( Fig. 12.2 ), which is much shorter than the delay at chemical synapses. Such nearly instantaneous transmission can be caused only by direct current flow between the cells. This current flows from the presynaptic cell through the gap junction channels and into the postsynaptic cell . Such direct flow of current does not occur at chemical synapses. Most electrical synapses are bidirectional: signals can be transmitted from either one of the connected cells to the other. In contrast, chemical synapses are unidirectional. The conductance of gap junction channels is regulated by two distinct gating mechanisms ( Box 12.2 ).
BOX 12.2
Two Distinct Gating Mechanisms in Gap Junction Channels
The conductance of gap junction channels is physiologically regulated. This is accomplished through channel gating, and at least two distinct gating mechanisms operate within each gap junction hemichannel. The first is Vj-gating, which depends on the junctional voltage ( V j ) across the gap junction. Vj-gating is responsible for rapid transitions between high and low conducting states of the channel. The low-conductance state that is entered as a result of Vj-gating does not completely close the channel. Hemichannels formed by some connexin isoforms close with depolarization; others close with hyperpolarization. The second type of gating mechanism involves slow transitions (10–30 msec) between the fully open and fully closed states. These slow transitions can be mediated by three distinct processes. First, slow transitions can occur in response to changes in voltage: this is called loop gating because it involves the extracellular loops that connect adjacent transmembrane domains in connexin. The loop gating voltage sensor and the Vj-gating voltage sensor are independent structures. Second, slow transitions can be caused by changes in pH or Ca 2+ ; this is called chemical gating. In cells that are normally coupled electrically and metabolically through gap junctions, an increase in [Ca 2+ ] i or a decrease in pH can close gap junction channels and uncouple the cells. This can serve as a protective mechanism, uncoupling damaged cells, which have elevated [Ca 2+ ] i or [H + ] i , from healthy cells. Finally, slow transitions can be mediated by the docking or undocking of two hemichannels.
Electrical synapses between neurons in the mammalian CNS play a role in neuronal synchronization because they allow the direct, bidirectional flow of current from one cell to the other. For example, electrical synapses coordinate spiking among clusters of cells in the thalamic reticular nucleus. Similarly, electrical synapses in the suprachiasmatic nucleus help synchronize spiking that may be necessary for normal circadian rhythm. Direct electrical communication between cells is also physiologically important outside the nervous system: for example, gap junction channels between heart cells enable the cells to depolarize and contract synchronously ( Chapter 14 ).
Most synapses are chemical synapses
At chemical synapses , the AP in the presynaptic nerve terminal releases neurotransmitter molecules that generate electrical or biochemical signals in the postsynaptic cells. Early in the 20th century, Henry Dale and Otto Loewi obtained critical evidence that dispelled doubts about chemical transmission. Dale showed that acetylcholine (ACh) was the most potent agent capable of mimicking parasympathetic nerve activation. His observation that the effects of ACh, injected into the bloodstream, were very rapid but short-lived led him to suggest that ACh was rapidly hydrolyzed. This presaged the discovery that the enzyme acetylcholinesterase terminates ACh action at synapses. Loewi subsequently demonstrated that stimulation of the vagus nerve to a frog heart released a substance into the bathing solution. When a different frog heart was immersed in this bathing solution, its rate slowed. a
Dale and Loewi shared the 1936 Nobel Prize in Physiology or Medicine for the discovery of chemical neurotransmission.
This chemical neurotransmitter, released by the vagus nerve, was later shown to be ACh. These discoveries laid the foundation for most of neuropharmacology and neurotherapeutics: agents that stimulate neurotransmitter release, mimic neurotransmitters, or interfere with their actions are among the most useful tools in the physician’s arsenal.
The application of electron microscopy and ultracentrifugation methods in the 1950s and 1960s led to important advances in understanding the structure and chemistry of synapses. Fig. 12.3 shows key structural features of a representative chemical synapse. The presynaptic terminal contains many small (∼40 nm diameter) round structures, the synaptic vesicles (SVs) , which contain high concentrations of neurotransmitters. SVs tend to concentrate at or near the active zone , a specialized region of the presynaptic plasma membrane (PM) that is involved in transmitter release. This region is closely apposed to the postsynaptic cell, with its own postsynaptic density region that is enriched with neurotransmitter receptors ( Chapter 13 ). At the synapse, the two cells are separated by a synaptic cleft 20 to 40 nm wide.
Neurons communicate with other neurons and with muscle by releasing neurotransmitters
When a nerve AP is conducted down the axon to the presynaptic terminal, the resulting depolarization triggers the Ca 2+ -dependent release of SV contents into the synaptic cleft. This process of exocytosis involves fusion of the SV membrane with the PM and the consequent emptying of the vesicular contents into the synaptic cleft. The SV membrane is then recycled.
Released neurotransmitter molecules diffuse across the synaptic cleft and interact with specific receptor molecules that are integral proteins in the PM of the postsynaptic neuron or neuroeffector cell. The interaction between the transmitter and its receptor can be characterized as a lock-and-key mechanism in which the transmitter (key) unlocks the receptor. This activates the receptor so that, depending on the receptor type ( Chapter 13 ), it either directly affects membrane conductance in the postsynaptic cell or, alternatively, initiates an intracellular signaling cascade that regulates a wide range of cellular processes including membrane conductance changes. These mechanisms modulate the postsynaptic neuron’s excitability (i.e., the ability to fire an AP).
Most synapses in the mammalian nervous system are chemical synapses. The number of presynaptic neurons that synapse onto one postsynaptic cell varies widely. For example, one skeletal muscle fiber is usually innervated by only a single motor neuron, whereas each motor neuron usually innervates more than one muscle cell. In contrast, as already noted, many presynaptic neurons may synapse onto a single postsynaptic neuron. Synapses are not static structures: new synapses can form, synaptic connections can be strengthened or weakened, and some synapses can be eliminated. This flexibility contributes to the enormous complexity, rich diversity, and remarkable plasticity of synaptic transmission that underlies higher brain function.
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