Synaptic Transmission


Synaptic Transmission

Communication between nerve cells occurs by the propagation of an action potential by one neuron down its axon and into the synaptic terminal where chemical neurotransmitters are released into the synaptic cleft.  These neurotransmitters diffuse across the cleft and bind to receptors on target neurons.  The activation of these receptors, in turn, activate ion channels that alter the membrane potential of the postsynaptic neuron.  These changes in membrane potential of the target neuron causes it to either generate action potentials for its own transmission of electrical impulses or is inhibited from doing so.  In this manner the process of synaptic transmission generates or inhibits electrical impulses in a network of neurons for the processing of information.


Structure of the Synapse 


In the process of synaptic transmission at least two cells participate: the cell releasing the chemical neurotransmitter, called the presynaptic cell, and the target cell receiving the signal, called the postsynaptic cell.  The presynaptic component of the synapse consists of the terminal ending, which contains vesicles called synaptic vesicles.  These vesicles, filled with chemicals referred to as neurotransmitters (or transmitters), fuse with the presynaptic membrane.  The fusion of the vesicle with the presynaptic cell membrane causes the release of the chemical neurotransmitters into the synaptic cleft.  The transmitters in turn act upon receptors located in postsynaptic cell membranes.  Synaptic contacts can be formed at different sites on the postsynaptic cell.  Those between axons and dendrites are called axodendritic synapses.  Contacts between axons and somata are called axosomatic synapses, and contacts between two axons are called axoaxonic synapses.  As will be discussed later, the location of the synapse on the postsynaptic cell plays a significant role in how information is transferred from cell to cell. 



Presynaptic Mechanisms of Chemical Transmission 



 
The process of synaptic transmission involves four phases: 1) the synthesis of the transmitter (panel a), 2) the storage and release of the transmitter (panels a and b), 3) the interaction of the transmitter with the postsynaptic receptor (panel b), and 4) the termination of synaptic transmission and reuptake of the transmitter (panel c) or its metabolism.  The biochemical mechanisms for synthesis differ for each neurotransmitter and will be considered in detail in later sections.  In general, however, each type of transmitter is packaged and stored in vesicles, which are then positioned for the release of their chemical transmitters into the cleft.

The release of the neurotransmitter is produced by the action potential when it invades the terminal ending.  The resulting change in the membrane potential activates voltage-sensitive Ca2+ channels, causing an influx of Ca2+ ions into the terminal.  By mechanisms not yet clearly understood, the Ca2+ ions cause the synaptic vesicles to fuse with the presynaptic membrane and release transmitter molecules into the synaptic cleft by the process of exocytosis.

Each synaptic vesicle releases a fixed, or quantum, number of neurotransmitter molecules.  Acetylcholine-containing vesicles, for example, have approximately 10,000 molecules per vesicle.  The number of synaptic vesicles that fuse with the synaptic membrane to release their chemical transmitters depends on the concentration of Ca2+ ions within the synaptic terminal.  Greater concentrations of Ca2+ within the terminal cause more vesicles to release their contents into the synaptic cleft.

The amount of Ca2+ within the terminal is regulated by the activity of the cell (that is, the number of action potentials it has generated).  As action potentials invade the synaptic terminal with greater frequency, there is a residual increase in Ca2+ ions within the terminal.  This increase in Ca2+ leads to a greater release of the neurotransmitter from the synaptic terminal.  In this manner, the frequency of action potentials produced by the nerve cell can govern the amount of chemical transmitter it releases.

 The amount of transmitter released can also be affected by extrinsic processes such as synaptic inputs from other cells that alter the calcium levels within the terminals.  The mechanisms of these axoaxonic inputs will be further discussed later.


Postsynaptic Mechanisms of Chemical Transmission 


 

After a chemical transmitter is released into the synaptic cleft, it can bind to a receptor located on the postsynaptic cell.  The coupling of the transmitter with the receptor causes the receptor to open, permitting the passage of specific ions through the membrane.  The receptor can directly activate the ion channel or indirectly activate it through a second messenger such as cAMP, cGMP, or IP3.

The movement of charged ions into or out of a postsynaptic cell can affect its membrane potential.  For instance, the activation of a neurotransmitter-sensitive ion channel that permits the influx of Na+ into the cell results in more positive charges inside of the cell.  This in turn depolarizes the cell, making the membrane potential more positive.  Likewise, the efflux of positive charges from the interior of the cell or the influx of negative charges into the cell hyperpolarizes it, causing the membrane potential to become more negative.

The properties of these chemically activated ion channels are quite different from those of the voltage-activated ion channels responsible for the action potential.  First of all, the chemically activated channels remain open as long as the transmitter is bound to the receptor.  Secondly, the chemically activated channels are generally not sensitive to changes in the membrane potential.

The activation of a single receptor results in the influx or efflux of one or more types of ion.  The number of ions that flow through the channel per unit time is referred to as the single channel current.  The synaptic current is made up of all the single channel currents through the membrane at the synapse.






The flow of synaptic current resulting from the release of transmitters from one vesicle produces a change in the membrane potential referred to as a unitary postsynaptic.  These postsynaptic potentials can summate, or act together, to depolarize or hyperpolarize the membrane.  Postsynaptic potentials that depolarize the membrane tend to excite the nerve cells to discharge action potentials and are therefore called excitatory postsynaptic potentials (EPSPs).  In contrast, postsynaptic potentials that hyperpolarize the membrane potential tend to prevent or inhibit the nerve cell from generating an action potential and are therefore called inhibitory postsynaptic potentials (IPSPs).







Excitatory Postsynaptic Potentials 

A number of ions are capable of producing EPSPs. We will first focus on the mechanisms involved in producing EPSPs by Na+ ions alone. The synaptic activation of a receptor that selectively allows Na+ to flow results in the influx of Na+ into the interior of the cell. The addition of more positive charges into the cell therefore depolarizes the membrane. The influx of Na+ ions is due to two factors: a concentration gradient and an electrical gradient. As we learned earlier, the concentration of Na+ ions is greater outside of the cell than inside; this concentration gradient moves Na+ ions into the cell. In addition, a membrane potential of -60 mV establishes a strong electrical gradient for the influx of Na+. The equilibrium potential for Na+ is typically +55 mV. As we previously discussed, the equilibrium potential is the membrane potential at which the movement of ions resulting from electrical forces is equal to the movement of ions-in the opposite direction-resulting from the concentration gradient. Since the value of the resting membrane potential is much less than the equilibrium potential for Na+, the electrical force will not be sufficient to counteract the inward flux of Na+ ions. In fact, the electrical driving force for Na+ aids in the inward influx of Na+ ions.

 The electrical driving force acting on a particular ion is the difference between the membrane potential and the equilibrium potential for that ion (Em - Eion).  In the case of Na+, this driving force is [-60 mV-(+55 mV)] or -115 mV (Panel a).  The negative value of the electrical driving force for Na+ aids in attracting Na+ ions into the cell. As a consequence, the concentration gradient and the electrical gradient both act to produce an influx of Na+.

 



Excitatory postsynaptic potentials can also be produced by the opening of channels that are somewhat nonselective and result in the simultaneous flow of both Na+ ions into the cell and K+ ions out of the cell.  This is characteristic of a type of acetylcholine receptor found at the junction between nerve and muscle cells.  How can an ion channel that allows positively charged ions such as K+ to flow out of a cell cause the membrane to depolarize? This occurs because more Na+ ions flow into the cell than do K+ ions out. At a resting membrane potential of -60 mV, the driving forces that influence the influx of Na+ ions are greater than those that affect the efflux of K+ ions. Like the Na+ ion, the forces acting on K+ produce K+ fluxes that act in the same direction, but in the case of K+ we have an outward flux. Moreover, the outward K+ flux is not as great as the inward Na+ flux.

The electrical force resulting from the difference between the resting potential and the equilibrium potential for K+ is [-60 mV- (-75 mV)] or +15 mV (Panel a). The positive value of the driving force results in an efflux of K+ ions. Together, the concentration and electrical forces act to move K+ ions from the interior of the cell outward (Panel b). From the calculation of electrical driving forces, however, we can see that the resulting magnitude of the K+ efflux is much smaller than the magnitude of the Na+ influx (Panel c). As a consequence, when this type of acetylcholine receptor is activated, the total influx of Na+ ions will be substantially greater than the efflux of K+ and will therefore result in the depolarization of the membrane.










Inhibitory Postsynaptic Potentials 


Action potentials are electrical impulses transmitted by nerve cells. They can be thought of as a change in the voltage of the membrane potential that causes it to go from its negative resting state to a positive value for a very brief time. This type of change in the membrane potential is typically found in nerve axons.  The figure shows the changes in the membrane potential that characterize the action potential.  The membrane potential is initially at its resting level of -60 mV.  As the membrane potential becomes more positive (a process called
depolarization), it reaches a threshold value at approximately - 45 mV.  After reaching threshold, the membrane potential rapidly changes to more positive values during a rising phase.  It reaches a peak at +25 mV and begins to repolarize.  In repolarization, the membrane becomes hyperpolarized, or more negative than in the original resting state. It remains hyperpolarized for a time before returning to the resting level of -60 mV.


Closing of Ion Channels by Receptors 

Our discussion of transmitter-receptor interactions has thus far focused only on the opening of ion channels. There is also a class of receptors, however, that close their ion channels when coupled to a transmitter. The closing of these chemically activated ion channels can also produce depolarization or hyperpolarizing changes of the membrane potential.

 For example, the closing of Na+ channels that are normally open prevents the influx of Na+ ions.  As a consequence, the efflux of K+ is the predominant effect, and the membrane hyperpolarizes.  In a similar fashion, transmitter-receptor interactions that close K+ channels prevent the efflux of K+ ions.  In this situation, the influx of Na+ predominates, and the membrane depolarizes.

 The mechanisms of transmitter-activated channel closings are typically carried out by second messenger systems from within the postsynaptic cell and last longer than transmitter mechanisms that involve the opening of ion channels.  The details of the ways in which channels close vary with different types of receptors and will be discussed in relation to their associated neurotransmitters.

Termination of Synaptic Transmission 

The termination of synaptic transmission occurs when the transmitter is removed from the synaptic cleft.  This process is accomplished in most neurotransmitter systems by the transport of the transmitter back into the presynaptic terminal.  A re-uptake mechanism pumps most transmitters back into the presynaptic terminal.  Other transmitters are removed from the synaptic cleft by degrading enzymes, and the metabolic products are then transported back into the presynaptic terminal.  As we shall see later the pumping mechanism is specific for each type of transmitter substance or metabolite and can be affected by selective drugs.

Recycling of Neurotransmitters 

After a transmitter has been transported back into the presynaptic terminal, it is again packaged into vesicles for storage in preparation for release.  In cases in which the metabolite is transported into the presynaptic terminal, the transmitter is resynthesized from the metabolic precursor and then packaged and stored into vesicles.  The repacking of the neurotransmitter is an energy-dependent process requiring ATP.  The details of this process will be discussed later in relation to the neurotransmitter, norepinephrine.


Diffuse and Discrete Chemical Synapses 

 

Chemical synapses have been shown to have either discrete or diffuse actions.  In discrete synapses, the chemical neurotransmitter is released from restricted areas of the presynaptic terminal, called active zones, into a small synaptic cleft; only 30 nm separate the pre- and postsynaptic membranes.  An example of a discrete synapse is the junction between nerve and striated muscle cells, which tend to activate a small region on the muscle fiber.

In diffuse synapses, on the other hand, transmitter release is not limited to specific active zones, and the distance between the presynaptic and postsynaptic membrane can be as much as 150 nm.  These synapses have the form of beads on a chain, called varicosities.  The varicosities are an extension of the axon and form an overlapping network of synapses en passant, or synapses in passage.  As the action potential invades each varicosity, vesicles fuse with the presynaptic membrane, and the action potential continues on to the next varicosity.  The effect of this type of synapse is to activate a large surface area of one cell or a large number of cells in a diffuse manner.  The diffuse synapse is typical of nerve terminals of the sympathetic autonomic nervous system and of nerve cells containing catecholamines within the central nervous system.


Electrical Synapses 

 

In addition to chemical synapses, other types of synapses can be formed between neurons such as electrical synapses.  The structure of the electrical synapse is similar to the bridge junctions or gap junctions seen in other cells.  Under the electron microscope, the membranes of two adjoining cells appear to be fused together.  Studies have shown that the pre- and postsynaptic cells are connected by a protein channel called a connexon that spans the gap between them.  The connexon is made of six protein subunits called connexin that are arranged into a hexagonal assembly.

Electrical synapses are found between axons and soma, axons and dendrites, dendrites and dendrites, and soma and soma.  These synapses are pathways for the direct conduction of ions from one cell to another.  In addition, the channels are large enough to allow the passage of molecules such as cAMP, sucrose, and small peptides.  Thus, these "electrical" synapses serve as channels for both electrical and metabolic communication.

In terms of electrical communication, these synapses synchronize the activity of many adjoining cells as well as provide a pathway for a rapid communication between cells.  Electrical synapses in the form of gap junctions are also found in cardiac cells of the heart, many smooth muscle cells, and other cells that display a synchronization of activity.


External Links to Related Topics

Synaptic transmission animation video


                                                                                                       
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