Chemical Synapses

At the ends of the terminal arborizations of the presynaptic nerve axon are the bulbs or boutons of chemical synapses. Each synaptic bulb is from 1 to 2 |im in diameter; it is filled with many spherical, synaptic vesicles containing neurotransmitter, some of which are in intimate contact with the membrane of the bulb facing the synaptic cleft or gap (Eccles, 1964). The vesicles are from 20 to 60 |im in diameter and are constantly being made by the metabolic machinery in the bulb and axon terminal. The size and shape of vesicles depends on the neurotransmitter being used. The 20 to 60 nm spherical vesicles are thought to be associated with excitatory synaptic coupling and the neurotransmitter ACh. Certain inhibitory boutons in the CNS have flattened vesicles, while spherical vesicles in central adrenergic boutons are larger (60 to 80 nm) and have electron-dense cores.

The details of presynaptic chemical synapse action are as follows:

1. In a resting bouton, a certain fraction of the vesicles filled with neurotrans-mitter molecules are docked to the inside of the active zone of the bouton (the membrane facing the synaptic cleft) at membrane fusion proteins. A small fraction of vesicles is free to move inside the bouton, but the majority of the vesicles are immobile, bound to one another and the inside of the bouton membrane by cytoskeletal filaments made from proteins called synapsins (Kandel et al., 1991, Ch. 13).

2. When a presynaptic action potential (spike) propagates down the terminal arborization to a bouton, the depolarization causes voltage-gated calcium channel proteins to "open," allowing Ca2+ to flow inward through the walls of the bouton. During an action potential, the [Ca++] inside the bouton at the active zone can rise a 1000-fold from about 100 nM to 100 |M.

3. The local increase in [Ca++] activates the protein, calmodulin, which in turn activates the protein kinase enzymes.

4. Three transient events follow the creation of active protein kinases. The cytoskeletal filaments dissolve, allowing bound vesicles to move toward the active zone. Vesicle motion toward the fusion proteins may in fact be guided by low-molecular-weight G-proteins. Vesicles bind to membrane fusion proteins. The membrane fusion proteins dilate, dumping the neu-rotransmitter in the bound vesicles into the synaptic cleft (Kandel et al., 1991). This process is illustrated in Figure 1.3-1.

The postsynaptic events of synaptic transmission begin with the nearly simultaneous release of the neurotransmitter (NT) from the bouton following the arrival of the presynaptic action potential. About 150 vesicles dump NT per presynaptic spike at a motor end plate, and from one to ten vesicles may be involved for interneuronal communication in the CNS. The "bolus" of NT diffuses rapidly across the 200-nm cleft. On the subsynaptic membrane (SSM) (e.g., on a dendrite) there are located many receptor proteins for that specific NT. Also present are molecules of an NT-esterase protein that rapidly destroys the free NT in the cleft. In the case of the NT ACh, cholinesterase breaks it down into acetate and choline. Choline is recycled by the metabolic machinery in the bouton; proteins in the bouton membrane actively transport

Synaptic bouton

Synaptic bouton

Ca channel

Chemical Synapse

t Alignment protein

Actin filaments t Alignment protein

Actin filaments

Chemical Synapse

Sub-synaptic Na+ channels

FIGURE 1.3-1 (A) Schematic of a synaptic bouton before the arrival of an action potential. Note that some small amount of NT leaks randomly from the vesicles docked at the presynaptic membrane, causing noise in the postsynaptic transmembrane potential. (B) Events occurring at the arrival of an action potential. Note that voltage-gated Ca++ channels open, NT is released, Na+ passes through the SSM NT-gated Na+ channels, and an epsp is generated.

Sub-synaptic Na+ channels

FIGURE 1.3-1 (A) Schematic of a synaptic bouton before the arrival of an action potential. Note that some small amount of NT leaks randomly from the vesicles docked at the presynaptic membrane, causing noise in the postsynaptic transmembrane potential. (B) Events occurring at the arrival of an action potential. Note that voltage-gated Ca++ channels open, NT is released, Na+ passes through the SSM NT-gated Na+ channels, and an epsp is generated.

choline into the bouton where the enzyme cholineacetyltransferase synthesizes ACh from acetyl coenzyme A and the free choline. This process is more complex that it sounds, because the ACh must be put into the vesicles in just the right amount.

When the nicotinic ACh receptor proteins on the SSM each bind with two ACh molecules, their conductance to [Na+] and [K+] increases transiently, allowing sodium ions to flow in and some potassium ions to flow out. The net result of about 200,000 receptor proteins being activated by ACh is the generation of a small transient depolarization of the SSM (an excitatory post synaptic potential or epsp). The peak amplitude of a normal epsp is about 5 mV. epsps are summed in time and space over a dendritic tree, and if the instantaneous sum is large enough, the post synaptic neuron generates an action potential on its axon (Figure 1.3-2).

Chemical Synapse Images

FIGURE 1.3-2 Schematic cross section of a nicotinic ACh NT synapse. Two molecules of ACh must bind to the proteins of the ACh-gated channels so that their conductance to Na+ and K+ increases. The resulting depolarization of the SSM causes voltage-gated Na+ channels to open, further depolarizing the SSM, forming an epsp.

FIGURE 1.3-2 Schematic cross section of a nicotinic ACh NT synapse. Two molecules of ACh must bind to the proteins of the ACh-gated channels so that their conductance to Na+ and K+ increases. The resulting depolarization of the SSM causes voltage-gated Na+ channels to open, further depolarizing the SSM, forming an epsp.

ACh can also affect inhibitory postsynaptic potentials (ipsps) at SSMs having a muscarinic receptor system. In this case, 1 molecule of ACh in the cleft combines with a single site on a muscarinic protein that projects through the subsynaptic membrane. As a result of the ACh binding, the muscarinic protein causes the a-subunit of a three-unit, G-protein complex to dissociate and bind with a potassium ion channel protein. The a-G*K+-channel protein association causes the K+ channel to open, allowing [K+] to flow outward. The outward potassium current causes the postsynaptic membrane potential at the synapse to hyperpolarize (i.e., go more negative). After a few milliseconds, the a-G protein dissociates from the K+-channel protein, allowing it to close (Figure 1.33). This type of ipsp generation is known to occur when the autonomic fibers in the vagus nerve that synapse with pacemaker cells in the heart are active; the heart slows as a result of this action. Far from Nature being consistent in her designs, in smooth muscle in the stomach, when ACh binds to subsynaptic muscarinic receptors, other elements of the G-protein complex are released and bind to K+ channel proteins, closing them. The reduction of the slow, outward, K+ leakage current causes the postsynaptic membrane voltage to depolarize in this case, leading to muscle contraction (Fox, 1996).

Another baroque scenario is seen in the action of the neurotransmitter norepinephrine (NEP), in both the central and peripheral nervous systems. In this case, one molecule of NEP in the synaptic cleft combines with its site on a receptor protein spanning the SSM. The binding of NEP with its site causes the a-subunit of the G-protein to dissociate. a-G then combines with the membrane-bound enzyme, adenylate cyclase, activating it. Adenylate cyclase causes the production of cyclic adenosine monophosphate (c-AMP) from ATP. c-AMP in turn activates protein kinase, which can open ion channels and produce other intracellular effects (Fox. 1996). Contrast the complexity of this six-step process with the simple, direct opening of nicotinic Na+ channels by ACh.

Protein Coupled Potassium Ach Channel

FIGURE 1.3-3 Schematic cross section of an SSM of an inhibitory synapse. One molecule of ACh binds to a muscarinic ACh receptor protein. This binding triggers the dissociation of an attached G-protein. The a portion of the G-protein diffuses to a receptor site on a potassium channel, where it causes an increase in gK. The outward flow of K+ ions causes the transmembrane potential to hyperpolarize toward the Nernst potential for potassium ions, causing an ipsp to be seen. This process is transient, and the resting conditions are slowly restored by enzymatic machinery that reassembles the G-protein and breaks down the ACh.

FIGURE 1.3-3 Schematic cross section of an SSM of an inhibitory synapse. One molecule of ACh binds to a muscarinic ACh receptor protein. This binding triggers the dissociation of an attached G-protein. The a portion of the G-protein diffuses to a receptor site on a potassium channel, where it causes an increase in gK. The outward flow of K+ ions causes the transmembrane potential to hyperpolarize toward the Nernst potential for potassium ions, causing an ipsp to be seen. This process is transient, and the resting conditions are slowly restored by enzymatic machinery that reassembles the G-protein and breaks down the ACh.

There are many neurotransmitters; some act excitatorily in one class of postsyn-aptic neuron and inhibitorily on others. Some NTs are well-identified, others are suspected, and some are found in invertebrates. They include but are not limited to ACh, epinephrine, NEP, dopamine, serotonin (5HT), histamine, glycine, glutamate, GABA, nitric oxide (NO, a gas), endorphins, and enkephalins. In addition, there are many neuroactive peptides found in the mammalian CNS, such as neuropeptide-Y (see Table 14.2 in Kandel et al., 1991).

The vertebrate retina is a neurophysiologist's garden of synapses and neurotransmitters. Known retinal inhibitory neurotransmitters include glycine and GABA. Excitatory NTs include ACh and glutamate; other substances, classed as neuromod-ulators, include dopamine and serotonin. Still other substances found in the retina whose roles have yet to be clarified include adenosine, substance P (a large-molecular-weight protein), NO, and somatostatin (also known as growth hormone inhibitory hormone, a short peptide usually associated with the hypothalamus) (Kolb et al., 1999).

The neurotransmitters glycine and GABA are associated with the generation of ipsps and the inhibition of firing in the postsynaptic neuron. Both these NTs cause chloride channels to open. Open chloride channels tend to drive the transmembrane potential toward the Nernst potential for chloride (approximately -70 mV), assuming the internal concentration of [Cl-] stays constant. The increased gCl resulting from the open chloride channels tends to clamp Vm ^ -70 mV, counteracting any depolarization caused by sodium epsps.

Glutamate is an excitatory NT in the CNS. There are four types of glutamate receptors, and of those there may be subtypes or variants. The first three are directly gated receptors. The NMDA receptor requires both a glutamate and a glycine molecule to open for Ca++ and Na+ (in), and K+ (out) currents. The Kainate receptor requires one glutamate molecule to allow Na+ (in) and K+ (out). The Kainate-Quisqualate-A receptor binds one glutamate molecule and has a site for Zn++ binding, too. It passes Na+ (in) and K+ (out). The quisqualate B receptor also binds one glutamate molecule, and uses a G-protein second-messenger system to open ion channels. Details on the biochemistry of these systems can be found in Kandel et al., (1991).

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