Chapter 8 - Synaptic Transmission and Neural Integration

Types of Synapses Synapse Animations
1. Electrical - Electrical synapses are due to gap junctions between cells that allow ions or secondary messengers to flow from one cell to another. Gap junctions are important in the transmission of signals among smooth and cardiac muscle cells. Recent studies indicate that gap junctions transmit some signals between neurons in the adult brain and are important in the development of the nervous system. 
2. Chemical - Most neurons communicate by means of neurotransmitters at chemical synapses. One neuron secretes a neurotransmitter into extracellular space upon the arrival of an action potential. The neurotransmitter binds to receptors in the plasma membrane receiving the signal. The cell membrane responds with a graded potential which may or may not initiate an action potential. 
     In this chapter we will examine synapses between neurons. A synapse between a neuron and an effector organ such as a muscle or a gland is called a neuroeffector junction. We will examine examples of these in future chapters. 
Functional Anatomy of Chemical Synapse 
   The neuron that transmits a signal to another neuron is the presynaptic neuron and the neuron that receives the signal is the postsynaptic neuron. The presynaptic axon terminal may synapse with the postsynaptic cell's: (Here, we will ignore the dendrodendritic synapses for the sack of simplicity.)
dendrite - axodendritic synapse
cell body (soma) - axosomatic synapse
axon terminal - axoaxonic synapse
   The presynaptic neuron releases neurotransmitter into a narrow space (30 - 50 nm) between the cells called a synaptic cleft. The neurotransmitter is contained in synaptic vesicles and is released by exocytosis. The neurotransmitter effects a change in the postsynaptic cell by a mechanism called signal transduction. 
   Concentrated at the axon terminal are voltage-gated calcium channels. The depolarization of the membrane associated with an action potential causes the calcium channels to open and Ca++ rushes down its electrochemical gradient. Ca++ causes the membranes of the synaptic vesicles to fuse with the cell membrane and releases its contents by exocytosis. (Go to the chemical synapse link on this site for an animation.)
   The Ca++ influx stops within a few msecs when the Ca++ channel close. However, when a series of action potentials arrives at the axon terminal there is a greater inflow of Ca++ and more neurotransmitter is released. Hence, the higher the frequency of action potentials the greater the amount of neurotransmitter released.
   The neurotransmitter is a ligand that binds to a receptor protein. The neurotransmitter needs to be removed to end the signal and clear the way for the next signal.
Processes for Neurotransmitter Removal  Norton books animation
1. Diffusion - Neurotransmitter may simply diffuse away.
2. Re-uptake - The presynaptic neuron may actively transport the neurotransmitter back into itself.
3. Enzymatic Destruction - Enzymes located in cell membranes of pre- and postsynaptic cells or glial cells may breakdown the neurotransmitter.
   It takes about 0.5-5 msec from the time of arrival of the action potential to a response in the postsynaptic cell this is called a synaptic delay and is due primarily to the time it takes for calcium to trigger exocytosis.
Signal Transduction Mechanisms
   Neurotransmitters can produce either a fast or a slow response. Fast response involves ionotropic receptors where the neurotransmitter binds to a channel-linked receptor. All channel-linked receptors are ligand-gated channels. The channel opens, the ions flow down their electrochemical gradients, and produce a brief change in membrane potential called a postsynaptic potential (PSP). Slow responses act by triggering biochemical changes through G protein-linked receptors. These are called metabotropic receptors.
   Activation of the G protein may either open or close an ion channel. The final effect depends upon the type of ion channel. If the result is a depolarization the response is excitation; if the result is hyperpolarization the effect is inhibition. 
   The G protein may either be directly coupled to an ion channel or may trigger the activation or inhibition through a secondary messenger system. The duration of the response may range from msec to hours. 
Excitatory Synapses
    An excitatory synapse causes a graded potential that depolarizes the membrane and brings it closer to threshold. The depolarization is an excitatory postsynaptic potential (EPSP) and may be either fast or slow. 
    Fast EPSP's involve the opening of small cation channels (for K+ and Na+). Because there is a larger influx of Na+ compared to K+ a net depolarization results.
   Slow EPSP typically involve the closing of K+ channels through the mediation of a G protein and cAMP as a second messenger. The decrease in K+ permeability causes the net influx of positive charge (associated with Na+) to increase which depolarizes the membrane. These EPSP take longer to develop and last longer.
Inhibitory Synapses
   An inhibitory synapse decreases the likelihood that an action potential  will occur by either hyperpolarizing the membrane or keeping it at the resting level.
   At inhibitory synapses the neurotransmitter opens channels for either K+ or Cl- . Opening K+ channels causes K+ to leave the cell hyperpolarizing the membrane and creating an inhibitory post-synaptic potential (IPSP). The effect of a neurotransmitter that opens Cl- channels depends upon the electrochemical force acting upon Cl-
    In some neurons Cl- are actively transported out of the cell. This creates an equilibrium potential for Cl- that is more negative than the resting potential. In these cells there is an electrochemical force driving Cl- into the cell. When the Cl- channels are opened, Cl- goes into the cell down its gradient and hyperpolarizes it (make it more negative).
    In other neurons there is no active transport of Cl- and Cl- is at equilibrium. The way the opening the Cl- channels in these cells is inhibitory is more complicated. 
    The opening of the Cl- channels interferes with the ability of excitatory synapses to induce EPSP's. This is because if the Cl- channels open at the same time as the cation channel that produces an EPSP, Cl- moves into the cell as the membrane potential becomes more positive. The movement of negatively charged Cl- then cancels out the change that would have resulted from the influx of positive charges. As a result, the membrane potential does not change and threshold is not reached.
Neural Integration
   The axon hillock of the postsynaptic neuron is influenced by the electrotonic conduction of all the membrane potential changes produced by the various excitatory and inhibitory synapses. The net change in membrane potential at the axon hillock that results from this process is called neural integration. Whether or not the potential at the axon hillock reaches threshold depends upon the additive effects of all the graded potentials. The graded potential can either add in time or space. 
Temporal Summation
   In temporal summation postsynaptic potentials at the same synapse occur in rapid succession. Because the effect of the first potential does not have time to dissipate the succeeding potentials add to the previous ones and increase the change in potential. Summation can occur with IPSP's as well as with EPSP's. 
   Temporal summation can occur because postsynaptic potentials last longer than action potentials. Neurotransmitter released into the synaptic cleft by a previous action potential may still be present when a succeeding action potential causes the release of more neurotransmitter.
Spatial Summation 
      In spatial summation multiple postsynaptic potentials from different synapses occur about the same time and sum. The EPSP's of different synapses are not strong enough to generate an action potential but by reinforcing one another may trigger an action potential. It is important to keep in mind that EPSP's and IPSP's will also add up to cancel each other's effects.
  
Frequency Coding
   Neural integration of postsynaptic potentials not only triggers action potentials but also affects the frequency of action potentials when summation results in a suprathreshold potential. The relationship between the strength of suprathreshold stimuli and the frequency of action potentials is called frequency coding.
Presynaptic Modulation
   With axoaxonic synapses the neurotransmitter from the presynaptic neuron modulates the axon terminal by affecting the amount of calcium that enters in response to an action potential.
Presynaptic Facilitation 
     Presynaptic facilitation results when an axoaxonic synapse causes an action potential arriving at the postsynaptic axon terminal  to release more neurotransmitter and thereby cause a larger EPSP. Note that this type of synapse only influences the effect of another neuron at its synapse with a postsynaptic neuron. In other words, presynaptic modulation will only affect transmission to the postsynaptic neuron at one specific synapse.
  
Presynaptic Inhibition 
     In presynaptic inhibition the neurotransmitter from the presynaptic neuron at the axonic synapse causes the postsynaptic axon terminal to release less neurotransmitter when an action potential arrives.
  
   It is important to keep in mind that presynaptic modulation can affect inhibitory synapses as well as excitatory synapses.
Neurotransmitters (Table 8.1)
Acetylcholine (ACh) 
   Found in both central and peripheral nervous systems. It is the most abundant neurotransmitter in the peripheral nervous system. ACh is synthesized in the cytoplasm of the axon terminal from two substrates, acetylCoA and choline, in a reaction catalyzed by choline acetyl transferase.
    ACh is stored in synaptic vesicles until an action potential causes its release by exocytosis. ACh binds to receptors called cholinergic receptors and is degraded by acetylcholinesterase (AChE), an enzyme that can be found in both the pre- and postsynaptic membranes. The degradation products are acetate which enters the blood and choline which is taken up by the presynaptic neuron and recycled.
   There are two types of receptors for ACh:
1. Nicotinic cholinergic receptors are ionotropic and open channels for small cations (Na+ + K+) causing EPSP. Nicotinic receptors are located in the peripheral nervous system in certain autonomic neurons; on skeletal muscles; and in some regions of the central nervous system.
2. Muscarinic cholinergic receptors are metabotropic receptors operating through G proteins. The G protein may either open or close an ion channel or activate an enzyme depending upon the postsynaptic neuron in question. These receptors are found on some effector organs of  the autonomic nervous system and are the dominant cholinergic receptor in the central nervous system.
Biogenic Amines
   Biogenic amines are derived from amino acids and contain an amine group -NH2. The amines include catecholamines (dopamine, norepinephrine and epinephrine), serotonin and histamine. All are synthesized in the cytosol of the axon terminal.
   The different catecholamines bind to specific receptors. The receptors for dopamine are called dopaminergic. The receptors for epinephrine and norepinephrine are adrenergic because epinephrine and norepinephrine are also  know as adrenalin and noradrenalin.
   Among the adrenergic receptors there are two main classes, alpha adrenergic and beta adrenergic receptors. Each has its own subclasses   a1,  aand     b1,  b2,   b3.
   Catecholamines generally produce slow responses through G proteins 
   Following their release catecholamines are degraded by monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT).  
   Serotonin is found in the brain stem and some of its functions include regulating sleep and emotions.
  Histamine (also associated with allergic reactions) functions as a neurotransmitter in the hypothalamus.      
Amino Acid Neurotransmitters
   Amino acid neurotransmitters are the most abundant class of neurotransmitters in the central nervous system. Aspartate and glutamate are excitatory neurotransmitters while glycine and GABA (gamma-aminobutyric acid) are inhibitory.
Neuroactive Peptides
   Neuroactive peptides are short chains of amino acids. Many neuropeptides are known as hormones such as:
TRH (thyroid releasing hormone) which releases TSH
Vasopressin (ADH)
Oxytocin
Substance P
Endogenous opioids including enkephalins and endorphins
   Most neuropeptides are secreted from the same axon terminals as other neurotransmitters and act on metabotropic receptors to modulate the response of the postsynaptic neuron to the other neurotransmitters. 
Other Neurotransmitters
   Nitric oxide cannot be stored as it easily crosses the cell membrane as soon as it is synthesized. Its release is controlled by controlling its synthesis in a reaction catalyzed by nitric oxide synthetase. NO acts by altering the activity of proteins.
   ATP also serves as a neurotransmitter.