Neurophysiology Modules

Module 4: Synaptic Transmission

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Introduction

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Release of Neurotransmitter from a Nerve Terminal

Neurotransmitters are chemicals that transmit signals from one neuron to the next. Neurotransmitters are packaged into vesicles located in the nerve terminal. When an action potential depolarizes the nerve terminal, voltage-gated Ca2+ channels are opened, allowing Ca2+ to enter the terminal. When the calcium ions enter the presynaptic terminal, they bind with special protein molecules on the inside surface of the presynaptic membrane, called release sites. This binding in turn causes the release sites to open, allowing a few transmitter vesicles to release their transmitter into the synaptic cleft (space between a nerve terminal and the dendrites or soma of another neuron). The released neurotransmitter binds to receptors on the dendrite or soma of the postsynaptic neuron.

Let's make sure the terminology is clear:

• Synapse: a junction between two nerve cells, where information is transmitted chemically across a small gap (or synaptic cleft)
• Presynaptic neuron: the neuron that releases neurotransmitter at a synapse
• Postsynaptic neuron: the neuron with receptors for the released neurotransmitter

The nature of information processing by the nervous system requires that neuronal signaling occur over a very short temporal period. When an action potential reaches the nerve terminal, the neurotransmitter that is released must have only a transient effect on the postsynaptic neuron. This is accomplished by removing the neurotransmitter from the synaptic cleft soon after it is released. There are two main mechanisms through which this is completed:

• Chemically degrading the neurotransmitter with an enzyme
• Reuptaking it into the presynaptic neuron

Postsynaptic Actions of Neurotransmitters

Neurotransmitters have one of two general effects when they bind to postsynaptic receptors:

• They directly cause the opening of an ion channel
• They activate a second messenger system

There are several types of second messenger systems. One of the most common types entails the activation of G proteins. In the example below, the inactive G protein complex in the cytosol consists of guanosine diphosphate (GDP) plus three components: an alpha (α) component that is the activator portion of the G protein, and beta (β) and gamma (γ) components that are attached to the alpha component. As long as the G protein complex is bound to GDP, it remains inactive. When the receptor is activated by a neurotransmitter, the receptor undergoes a conformational change, exposing a binding site for the G protein complex, which then binds to the receptor. This causes the α subunit to release GDP and simultaneously bind guanosine triphosphate (GTP) while separating from the β and γ portions of the complex. The separated α-GTP complex is then free to move within the cytoplasm and have a number of potential effects.

Although a particular second messenger system can cause different effects in different neurons, one or more of the following effects are induced (as indicated in the diagram above):

1. Specific ion channels are opened
2. cAMP or cGMP are activated, resulting in the activation or deactivation of enzymes
3. One or more enzymes are directly activated
4. Gene transcription is altered

Excitatory and Inhibitory Neurotransmitters

Although neurotransmitters can elicit a number of complex changes in the postsynaptic neuron, often these effects are categorized as excitatory or inhibitory. After all, the key aspect of neuronal signaling is the generation of action potentials, so it is logical to divide neurotransmitter effects into those that:

• increase the probability that an action potential will be produced at the axon hillock (excitatory neurotransmitters)
• decrease the probability that an action potential will be produced at the axon hillock (inhibitory neurotransmitters)

For example, an excitatory neurotransmitter could open a ligand-gated Na+ channel and cause depolarization of the neuron, decrease conductance through K+ channels, or induce the synthesis of additional ligand-gated Na+ channels. An inhibitory neurotransmitter could open Cl- channels and cause hyperpolarization of the neuron, increase conductance through K+ channels, or induce the synthesis of additional K+ leak channels.

Postsynaptic Potentials

Although neurotransmitters can elicit complex postsynaptic effects, often they cause sudden changes in ionic movements across the membrane. These ionic movements produce the postsynaptic potentials that are added at the axon hillock; if the addition amounts to a sufficient depolarization, an action potential will occur.

Excitatory postsynaptic potentials (EPSPs) occur when positive ions enter the neuron or negative ions leave. In most cases, the EPSP is a result of opening of cation channels that allow both Na+ and K+ to pass across the membrane. However, the conductance for Na+ usually predominates, such that a depolarization occurs in the neuron. Inhibitory postsynaptic potentials (IPSPs) occur when negative ions (such as Cl-) enter the neuron or positive ions leave.

As an EPSP or IPSP propagates passively down a dendrite, it is altered by the physical properties of the neuronal membrane. This distorts the shape of an EPSP or an IPSP, so that if the electrical potential was recorded at a distance from the synapse where the potential was generated, it would look quite different that near the synapse. By use of cable theory, the change in the properties of an EPSP or IPSP as it moves down a membrane can be modeled mathematically. However, this is certainly beyond the scope of this course.

WHAT DO I NEED TO KNOW?

First, you should be aware that due to the membrane properties of a neuron, the amplitude of an EPSP or IPSP decreases as the potential propagates down the membrane, and the potential becomes more prolonged. Thus, if an EPSP is generated by Na+ ions entering a distal dendrite, then the depolarization (change in voltage) will be tiny by the time it reaches the axon hillock.

In other words, ions entering (or leaving) at a synapse on a distal dendrite will have little impact on the change in membrane potential at the axon hillock, and thus won't play very much of a role in determining whether the neuron will produce an action potential. In contrast, ions entering or leaving a neuron at a synapse on the soma will have a much bigger effect on the membrane potential at the axon hillock, and will play an appreciable role in determining whether the neuron produces an action potential.

The axon hillock is constantly "summating" the thousands of EPSPs and IPSPs that are generated in the dendrites and soma. If this summation amounts to a depolarization of sufficient magnitude, the activation gates of the voltage-gated Na+ channels will open, an action potential will occur, and the neuron will release neurotransmitter onto the neurons it synapses upon. When the depolarization at the axon hillock is smaller than the threshold required to open the activation gates of the voltage-gated Na+ channels, the neuron will not communicate with other neurons down the line. Whether or not a neuron communicates with other neurons all comes down to the membrane potential at the axon hillock at a particular time.

Some Synapses Are Different

Most synapses are axo-dendritic (i.e., the synapse is on a dendrite) or axo-somatic (i.e., the synapse is on the neuronal soma), as described above. However, other synaptic configurations also exist. One such configuration is the axo-axonic synapse, where an axon of one neuron synapses on the axon of another neuron.

What is the function of an axoaxonic synapse? One common role of such synapses is producing presynaptic inhibition. The axoaxonic synapse can activate a second messenger system that affects the voltage-gated Ca2+ channels at the nerve terminal, so they allow less Ca2+ to enter the nerve terminal after an action potential occurs. As a result, the neuron releases less neurotransmitter following an action potential. Axoaxonic synapses thus provide a mechanism to regulate how much a neuron communicates to other neurons. Afferent fibers entering the spinal cord are subject to presynaptic inhibition via axoaxonic synapses. A similar phenomenon is presynaptic facilitation. Second messenger systems triggered through axoaxonic synapses can cause more calcium to enter the nerve terminal when an action potential occurs, so a neuron releases more neurotransmitter. It is believed that presynaptic facilitation plays a key role in learning and memory.

Although we normally think of neurotransmitters binding to postsynaptic receptors, some nerve terminals have autoreceptors for the neurotransmitter they release. Often these autoreceptors play a homeostatic role, and serve to adjust the amount of neurotransmitter released subsequently. In other words, autoreceptors serve to assure that a nerve terminal is not releasing too much, or too little, neurotransmitter.

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Categories of Neurotransmitters

The most common neurotransmitters are amino acids, particularly glutamate, GABA (gamma-aminobutyric acid), and glycine. The actions of these amino acids will be discussed in subsequent modules. Glutamate is an excitatory neurotransmitter, and is released by most sensory afferents as well as neurons in the central nervous system. GABA and glycine are inhibitory neurotransmitters; glycine is mainly released from spinal cord neurons, whereas GABA is released from neurons in many brain areas. In fact, GABA is the most common inhibitory neurotransmitter present in the central nervous system.

Another very common neurotransmitter is acetylcholine. Acetylcholine is released by neurons in many brain regions, as well as by motoneurons, sympathetic and parasympathetic preganglionic neurons, and parasympathetic postganglionic neurons. Acetylcholine is mainly an excitatory neurotransmitter, although there are some examples where it has an inhibitory role (e.g., parasympathetic postganglionic nerve fibers that lower heart rate).

Another group of important neurotransmitters are the monoamines, chemicals that contain one amino group that is connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). The monoamine neurotransmitters include dopamine, norepinephrine, and serotonin. Monoamine neurotransmitters typically bind to G-protein coupled receptors, such that they can produce a wide variety of effects in the postsynaptic neuron. Many neurons that release monoamine neurotransmitters branch extensively, such that each neuron makes synapses on a large number of postsynaptic neurons. Many neurological and psychiatric diseases are related to the monoamine neurotransmitters.

Nitric oxide (NO) is released by nerve terminals in areas of the brain responsible for long-term behavior and memory. NO is different from other small-molecule transmitters, as it is very lipophilic and cannot be stored in the nerve terminal. Instead, it is synthesized as needed and then diffuses out of the presynaptic terminals to affect adjacent neurons. NO usually does not alter the membrane potential, but instead changes intracellular metabolic functions that modify neuronal excitability for seconds, minutes, or perhaps even longer. NO is also an important signaling molecule in the cardiovascular system, as you will learn in August.

A variety of peptides called neuropeptides can also act as neurotransmitters, but they usually have very specialized functions. For example, some hypothalamic neurons release peptides that control the release of hormones from the anterior pituitary. In some cases, a peptide hormone is co-released with one of the "classical" neurotransmitters discussed above.

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