Synapse: Meeting Point Between Neurons
Silvia Helena Cardoso, PhD

An understanding of synaptic transmission is the key to understanding the basic operation of the nervous system at a cellular level. Without transmission, there is no direct communication between cells - there would be only individual isolated cells. The whole point of the nervous system is to control and coordinate body function and enable the body to respond to, and act on, the environment. Synaptic transmission is the key process in the integrative action of the nervous system (1).

Synaptic transmission is the process at synapses by wich a chemical signal (a transmitter) is released from one neuron and diffuses to other neurons or target cells where it generates a signal which excites, inhibits or modulates cellular activities. By means of synaptic transmission, an electrical signal in one neuron passes from the terminal to its axon into another cell and starts in that cell an impulse having characteristics different from its own (2).

Since neurons form a network of electrical activities, they somehow have to be interconnected. This connection is not a simple continuity of cytoplasm, so that every neuron has electrical continuity with all others, as happens with simple wiring, but is carried out by very specialized and complex structures called
synapses. A synapse is the place where two neurons join in such a way that a signal can be transmitted from one to the other. The typical and overwhelmingly most abundant type of synapse is the one in which the axon of one neuron activates a second neuron, usually making a synapse with one of its dendrites or with the cell body. There are two ways in which this can happen, one is by the coupling of ion channels at the synapse, creating a passage way for the traveling ionic flux of the action and membrane potentials, which is called an electrical synapse, and the other is by a much more complicated way called a chemical synapse. In the case of the chemical synapse, the two neurons are not in strict contact, but have a small gap between them called the synaptic cleft. The signal is transmitted when one neuron releases a chemical (called neurotransmitter) into the synaptic cleft which is detected by the second neuron thru activation of receptors placed exactly opposite to the release site. The binding of the neurotransmitter to the receptors causes a series of physiological changes in the second neuron which constitutes the signal. Usually the release from the first neuron (called presynaptic) is caused by a series of intracellular events evoked by a depolarization of its membrane, and almost invariably when an action potential takes place.

As an electrical impulse arrives at the terminal, it triggers vesicles containing a neurotransmitter to move toward the terminal membrane . The vesicles fuse with the terminal membrane to release their contents. Once inside the synaptic cleft (the space between the 2 neurons) the neurotransmitter can bind to specific proteins on the membrane of a neighboring neuron.

What are the properties that a chemical synapse must have in order to carry out its functions?

There are four basic properties that all synapses share:
1. the presynaptic endings must store the transmitter
2. the ending must rapidly release the trasnmitter in response to stimulation by an action potential or more generally by depolarization
3. the trasnmitter must reach the target cell and cause a response
4. the action of neurotransmitter must be terminated promptly and the synapse must quickly prepare for a new stimulus.

Parts of a chemical synapse
The pre- and postsynaptic membrane at chemical synapses are separated by a synaptic cleft. The presynaptic side of the synapse, is usually an axon terminal. The terminal typically contains of small membranes-enclosed spheres, called synaptic vesicles. These vesicles store neurotransmitters, the chemical used to communicate with the postsynaptic neuron. Many axon terminals also contain larger vesicles, called secretory granules.

What triggers the release of a neurotransmitter?
Some mechanism must exist whereby the action potential causes the transmitter stored in synaptic vesicles to be expelled into the cleft.

When an action potential arrives at a synaptic ending, it causes the release of transmitter which is stored inside tiny vesicles called synaptic vesicles. A subpopulation of these vesicles are concentrated on the inside of the plasma membrane facing the synaptic cleft. The action potential stimulates de influx of Ca2+, which causes synaptic vesicles to attach to the release sites, fuse with the plasma membrane and expel their supply of transmitter. The transmitter diffuses to the target cell, where it binds to a receptor protein on the external surface of the cell membrane. The interaction of the transmitter and receptor stimulates the cell. After a brief period the transmitter dissociates from the receptor and the response is terminated. In order to prevent the transmitter from rebinding to the receptor and repeating the cycle, the transmitter is either destroyed by degradative action of an enzime or it is taken up, usually into the presynaptic ending.

The effects of the transmitter on the target cell may be excitatory, inhibitory ou modulatory. The typical or classic postsynaptic response is a fast local change in the local change in the electrical prperties of the postsynaptic membrane that is mediated through a change in the ionic permeability of the membrane. A cell is inhibited when the transmitter stimulus makes it harder to excite the cell and generate action potentials.
 

1.Neuron's dendrites; 2.neuron;  2a. nucleus. Axons (3) are the main conducting unit of the neuron. The axon hillocks  (2b) is  the site at which the cell's signs are initiated.  (6) Schwann cells, which are not a part of a nerve cell, but one of the types of glial cells, perform the important function of insulating axons by wrapping their membranous processes around the axon in a thight spiral, forming a myelin sheath (7), a fatty, white substance which helps axons transmit messages faster than unmyelinated ones.The myelin is broken at various points by the nodes of Ranvier (4), so that in cross-section it looks rather like a string of sausages. Branches of the axon of one neuron (the presynaptic neuron) transmit signals to another neuron (the postsynaptical cell) at a site called the synapse (5). The branches of a single axon may form synapses with as many as 1000 other neurons.

When a message comes in at one end of a nerve cell, an electrical impulse travels down the "tail" of the cell, called the axon, and causes the release of the appropriate neurotransmitter. Molecules of the neurotransmitter are sent into the tiny space between nerve cells, called the synaptic cleft (see text below).

 
 
 

Diagram and mycrography of a synapse of the neuromuscular junction of a fruit fly.1- Synaptic vesicles; 2- Presynaptic neuron (terminal axon); 3- Synaptic cleft; 4- Postsynaptic neuron.   Photo: From Synaptic function, by Kendal Broadie, PhD, Univ. Utah. Reproduced with permission. Diagram: Silvia Helena Cardoso, PhD. Univ. Campinas, Brazil.

 
 
 

Messages are passed from neuron to
                   neuron through synapses, using
                   chemicals called neurotransmitters.
                   Synapses are very small gaps between
                   neurons. To transmit a message across
                   a synapse in response to an incoming
                   action potential, neurotransmitter
                   molecules are released from one neuron,
                   the 'pre-synaptic' neuron, and diffuse
                   across the gap to the next neuron, the
                   'post-synaptic' neuron. Once there, the
                   neurotransmitter causes a new action
                   potential to be formed, and the process
                   begins again to carry the message to its
                   destination. Amazingly, a single axon
                   can form synapses with as many as
                   1,000 other neurons.

The synaptic junction between neurones

1. Bridging the information gap between neurones

Neurotransmitters are responsible for transmitting information across the synaptic gap
between neurones.

Neurotransmitters are stored in synaptic vesicles. When action potentials are conducted
down an axon:

      synaptic vesicles attach themselves to the presynaptic membrane, then
      break open and spill neurotransmitter into the synaptic cleft.

Neurotransmitters in the synaptic cleft :

      attach to postsynaptic receptor sites and trigger an action potential in the
      postsynaptic membrane
      some neurotransmitter attaches to presynaptic receptors (autoreceptors) located on
      the membrane (pre-synaptic membrane) of the cell that originally released them
 

There, one or more of six things can occur for each molecule:

1. It may "bind" (attach) to the receptors in the adjacent nerve cell, sending the message on, then leave the receptor, repeat Step 1, or go on to one of the other steps;
2. It may hang around in the synapse until a receptor becomes available, and then bind to it, release, and continue with Steps 1-3 until its activity is ended by Step 4, 5 or 6;
3. It may bind (attach) to the first cell's autoreceptors, which tell that cell not to release any more of the neurotransmitter molecules, then leave the autoreceptor and continue trying to bind again somewhere until its activity is ended by Step 4, 5 or 6;
4. It may be rendered inactive by an enzyme;
5. It may be reabsorbed by the first cell in the "reuptake" process, and recycled for later use or deactivated there; or
6. It may diffuse out of the synapse and be deactivated elsewhere.

1. The nerve cells (neurons) might not be manufacturing enough of a neurotransmitter
2. Too many molecules of the neurotransmitter are being dissolved or deactivated by enzymes
3. Too much of a neurotransmitter is being released
4. The molecules are being reabsorbed too quickly by the reuptake transporters

The autoreceptors are being activated too soon, shutting down the release of neurotransmitter molecules prematurely

The functioning of the brain depends on the flow of information through elaborate circuits consisting of networks of neurons. information is transferred from one cell to another at specialized points of contacts: the synapses.

The sending neuron releases chemicals called neurotransmitters into the synaptic cleft, the space between the two neurons. These chemicals excite receptors on the receiving neuron, causing an impulse to propagate along the second neuron.

When an action potential arrives at a synaptic ending, it causes the release of transmitter which is stored inside tiny vesicles called synaptic vesicles. A subpopulation of these vesicles are concentrated on the inside of the plasma membrane facing the synaptic cleft. The action potential stimulates an influx of Ca++, which causes synaptic vesicles to attach to the release sites, fuse with the plasma membrane and expel their supply of transmitter (fig). The transmitter diffuses to the target cell, where it binds to a receptor protein on the external surface of the cell membrane. The interaction of the transmitter.
 
 

When the electrical signal reaches the tip of an axon, it stimulates presynaptic vesicles located at nerve endings. These vesicles contain chemicals called neurotransmitters, which are released into the microscopic space between neurons (the synaptic cleft). The neurotransmitters attach to specialized receptors on the surface of the adjacent neuron. This stimulus causes the adjacent cell to wake up (to depolarize) and propagate an action potential of its own. The duration of a stimulus from a neurotransmitter is limited by the breakdown of the chemicals in the synaptic cleft and the reuptake by the neuron that produced them. Many carry messages that convey facts about the outside world - incomng sounds, patterns of light and so on - and integrate them into useful information. Some neurotransmitters also carry messages of action, telling muscles when to release or contract. Formerly, each neuron was thought to make only one transmitter, but recent studies have shown that some cells make two or more.

The sending neuron releases chemicals called neurotransmitters into the synaptic cleft, the space between the two neurons. These chemicals excite receptors on the receiving neuron, causing an impulse to propagate along the second neuron.

When an action potential arrives at a synaptic ending, it causes the release of transmitter which is stored inside tiny vesicles called synaptic vesicles. A subpopulation of these vesicles are concentrated on the inside of the plasma membrane facing the synaptic cleft. The action potential stimulates an influx of Ca++, which causes synaptic vesicles to attach to the release sites, fuse with the plasma membrane and expel their supply of transmitter (fig). The transmitter diffuses to the target cell, where it binds to a receptor protein on the external surface of the cell membrane. The interaction of the transmitter
 
 

3. The Terminal Button is the end-point of an axon that forms the presynaptic neuron.

 Advanced
 

The terminal button typically contains a number of subcellular structures (organelles) that support the synaptic process of interneuronal communication. Mitochondria are
available for energy production, and microtubules, which transport molecules between the soma and the terminal button, are present. In addition, extensions of the Golgi
apparatus (cisterna) make use of pieces of the presynaptic membrane to form the synaptic vesicles for neurotransmitter storage. This takes place via a process called
pinocytosis: pinching off a segment of the cell membrane.

Electrical synapses at specialized gap junctions where cell membrane is separated by 3 nm

            direct electrotonic spread of electrical current via intercellular connexon channels,
            widespread in invertebrate CNS, foetal/neonatal CNS and between glial cells, minor component of connections between mature vertebrate CNS neurones.
            spread of signals is very fast and secure
            connexon channel is large and passes all ions, so polarity of signal depends on initial signal

Chemical synapses at specialized synapses where cell membrane is separated by 20-50 nm

            a chemical molecule, the neurotransmitter is released from a specialized presynaptic site (electron-dense active zone) by vesicular fusion with the presynaptic
            membrane
            the neurotransmitter diffuses across the gap (synaptic cleft)
            the neurotransmitter binds to receptors on the postsynaptic membrane (electron-dense postsynaptic density)
            receptor activation directly or indirectly causes the opening of an ion channel

Neuromuscular junction (Lavidis)

            postsynaptic response is always excitatory
            always releases acetylcholine
            postsynaptic response is always direct (ionotropic receptor) and fast
            always secure - presynaptic action potential in a single terminal always causes postsynaptic action potential
            large number (100s) of active zones in each synaptic terminal

            large number of postsynaptic receptors in post-junctional fold

CNS synapses- are NOT the neuromuscular junction! Here is why -

            postsynaptic response can be excitatory or inhibitory

            Can release a wide variety of neurotransmitters
            postsynaptic response may be direct and fast (ionotropic receptor) or indirect and slow (metabotropic receptor)

            very insecure - a single action potential in a synaptic terminal rarely causes a postsynaptic action potential. Exceptions to this do occur in CNS.
            usually only one or a small number of active zones in each synaptic terminal
            may be a small/limiting number of postsynaptic receptors (controversial!!!); no post-junctional fold

CNS SYNAPTIC STRUCTURE

Presynaptic structures

            vesicles - contain amino acids or amines, release at synapse
            secretory granules (dense-cored vesicles) - contain peptides
            presynaptic densities - serve to organize vesicles and prepare them for release
            mitochondria

Postsynaptic structures

            postsynaptic densities - high density of receptors and ion channels, bind neurotransmitters and generate ionic currents

Wiring patterns

            axon terminal ends on a cell body = axosomatic synapse
            axon terminal ends on a dendrite = axodendritic synapse
            axon terminal ends on another = axon-axoaxonic synapse
            dendrite makes synapse with another dendrite = dendrodendritic synapse

Gray-type synapses

            Gray's type I synapse

            spherical lucent synaptic vesicles
            asymmetrical membrane differentiation - postsynaptic membrane is thicker
            usually uses glutamate and is excitatory in CNS

            Gray's type II synapse

            pleomorphic lucent synaptic vesicles
            symmetrical membrane differentiation - pre- and postsynaptic membranes are similar
            usually uses GABA and is inhibitory in CNS

Categories of chemical synapses

Excitatory synapses (excitatory postsynaptic potential = EPSP, current = EPSC)

            net effect of transmitter release is to depolarize the membrane
            typically opens Na+ or Ca2+ channels; channels may also pass K+
            most common CNS excitatory transmitter is glutamate

Inhibitory synapses (inhibitory postsynaptic potential = IPSP, current = IPSC)

            net effect of transmitter release is to hyperpolarize the membrane
            typically opens Cl- or K+ channels. Note that opening Cl- channels may have varying effects on membrane potential, depndending on the reversal potential for
            Cl- ions.
            most common CNS inhibitory transmitters are GABA (mid- and forebrain), glycine (hindbrain and spinal cord)

Fast ionotropic synapses

            have transmitter-gated ion channels as integral part of the receptor protein
            fast, electrical response to arrival of presynaptic action potential
            use amino acids, amines and ATP as neurotransmitters

Slow metabotropic chemical synapses

            can have ion channels indirectly coupled to receptor protein, via G-proteins +/- second messengers
            slow response following transmitter release (> 50 ms), activate second messenger system, not always a direct electrical effect
            may use amino acids, amines, or peptides

References
1. Cotman and MacGaugh - Behavioral Neuroscence.
2. Palay - MacGauh, 152