July 8, 2005

Neural Communication (the real thing)

Signals in unmyelinated axons.

Approximately 90% of the neurons in the brain are unmyelinated (that is, they are not insulated). Let's begin with the terminal bouton (presynaptic element).

1) In response to an action potential arriving at the terminal bouton, several events happen. The first is that voltage-dependent calcium (Ca2++) channels open. This allows Ca2++ to enter the terminal bouton (because of diffusion and electrostatic pressure).

2) Ca2++ then triggers the movement of synaptic vesicles to the membrane of the bouton where they fuse. This process is called docking. The membranes of both the vesicles and the terminal bouton contain clusters of proteins. It is at these clusters where the vesicles and the bouton join. Intracellular Ca2++ binds with these protein clusters causing them to move apart (called a fusion pore; looks like an elevator door opening). The neurotransmitter contained in the vesicle can now be released into the synaptic cleft where it diffuses toward the postsynaptic membrane.

3) Some of this neurotransmitter will be rendered inactive by enzymes present in the cleft. Some will be immediately sucked backed into the presynaptic terminal (a process called reuptake). Some of the neurotransmitter molecules will also bind with autoreceptors (special receptors on the presynaptic terminal that help to regulate the amount of neurotransmitter released--a kind of sensor whereby the presynaptic terminal can tell how much neurotransmitter that it has released and call a halt to the process). The message here is that the time window of opportunity for neurotransmitter to affect the postsynaptic membrane is limited.

4) But, here's the important part. Some of the neurotransmitter will bind with receptors located on the postsynaptic membrane (postsynaptic density on dendritic spine or dendritic shaft). These receptors can be of two forms, either ionotropic or metabotropic. Iontropic receptors are directly coupled with ion channels and in response to neurotransmitter binding will open the channels. Metabotropic receptors do the same thing but in an indirect way. The metabotropic receptor is coupled to a G-protein which activates a 2nd messenger (usually cyclic AMP; cAMP). The cAMP then causes the ion channel to open.

5) If the species of ion channel that opens is K+ (efflux) or Cl- (influx), then the membrane immediately around the channel will be hyperpolarized. The current that this generates is called an inhibitory postsynaptic potential (IPSP). If the species of ion channel that opens is Na+ (influx) or Ca2++ (influx), then the membrane immediately around the channel will be depolarized. The current that this generates is called an excitatory postsynaptic potential (EPSP).

6) In either case, the current (IPSP or EPSP) travels down the dendrite toward the cell soma. However, as this current moves down the dendrite, it degrades (becomes smaller) because as it moves it passes its charge to the next segment and then to the next segment. As each segment picks up charge, there is no influx or efflux of ions to rejuvenate the signal (remember that the ion channels are chemically-coupled at the receptor sites-- once your away from the receptor site, the current is on its own). Because the signal degrades over distance, IPSPs and EPSPs are said to be graded potentials. It's also often said that they are conducted along the dendrite according to cable properties (this term arose from the observation that transoceanic telephone signals degrade as they pass through the telephone cable under the ocean).

7) A single IPSP or EPSP arriving at the axon hillock would be insufficient to cause any change in the axon. If both an IPSP and an EPSP arrive at the axon hillock at the same time (or an IPSP arrives just a little bit earlier) then they would cancel each other out. However, neurons don't receive inputs from just one or two synapses . Neurons receive input from hundreds or thousands of synapses. So, if lots of EPSPs and only a few IPSPs arrive at the axon hillock (and the number of EPSPs is sufficient to depolarize the membrane potential to -50mV), then an action potential will occur (and neurotransmitter will be released to start the event in the next cell). If more IPSPs arrive, then the membrane will be hyperpolarized and no action potential will occur. This whole process is called neural integration.

So, why do the postsynaptic potentials degrade in amplitude (size) as they travel down the dendrites? The answer is pretty simple. First, there is resistance associated with the membrane. As the current moves down the dendrite, it encounters resistance which causes it to drop voltage (decrease in size). It's much like an individual trying to run through water. You run out of steam after awhile. So, why isn't the postsynaptic potential rejuvenated as it passes other ion channels along the length of the dendrite? The answer is that many of the sodium channels along the length of the dendrite are voltage-dependent. That is, they require a certain level of depolarization to open. The postsynaptic potentials are too small to affect them. There may also be ion channels on the dendrites that are ligand-dependent. That is, they are only activated when a neurotransmitter binds to the associated receptor. A postsynaptic signal generated somewhere else on the dendrite would not be able to affect these sites.

The Action Potential

Signals in unmyelinated axons

An action potential is generated at the axon hillock if sufficient numbers of EPSPs arrive at the site to depolarize the membrane above its threshold of excitation. An action potential moving down an unmyelinated axon is relatively slow because it takes time and energy to open ion channels at every step along the way. Fortunately, most unmyelinated axons are relatively short and this "slow" movement of the action potential is of little consequence.

Signals in myelinated axons

Signal generation in neurons with myelinated axons (generally longer axons) is exactly the same except that it is much faster. The reason it is faster is because it doesn't have to take the time and energy to constantly open and close ion channels at every step along the axon. Remember that myelination occurs in patches along the axon. So, the current generated by the action potential moves along these insulated stretches of the axon according to cable properties. When it reaches a bare patch (node of Ranvier), it is still of sufficent strength to cause Na+ channels to open and the new influx of Na+ rejuvenates the signal. If you were able to record the signal from a myelinated axon, it would look as if the action potential was jumping from node to node (called saltatory conduction).

Neurotransmitters

A variety of chemicals are secreted by neurons including neurotransmitters, hormones, and gases. generally speaking, these chemicals can be classified as either a neurotransmitter or a neuromodulator. The general distinction between the two is time. Neurotransmitters cause fast action while neuromodulators may provoke the same effect in the postsynaptic membrane but it takes them longer to do so. It's not always easy to tell a neurotransmitter and a neuromodulator apart. In fact, a chemical can serve as a neurotransmitter in one part of the nervous system and as a neuromodulator in another part of the nervous system.

Similarities between neurotransmitters and neuromodulators

1) Both are packaged in vesicles

2) Both are expelled from the cell through process of exocytosis

3) Both bind with specific receptors

While neurotransmitters either depolarize or hyperpolarize their target membrane, neuromodulators may do so. But, often they induce conformational changes in proteins which affect the ability of a neurotranmsitter to induce change (i.e., they change the system so that a neurotransmitter is either more likely or less likely to exert its effects).

Examination of the presynaptic terminal indicates that vesicles come in different shapes and sizes. Generally, large dense-core vesicles contain neuromodulators (peptides). Smaller vesicles contain neurotransmitter. Small vesicles may be either round or flattened. Round vesicles contain neurotransmitters that will depolarize the target membrane and are therefore called excitatory neurotransmitters. Flattened vesicles contain neurotransmitters which will hyperpolarize their target membrane and are thus called inhibitory neurotransmitters. The ultimate arbiter, however, of whether a neurotransmitter is excitatory or inhibitory is determined by the ion channel that is coupled to the receptor. If neurotranmitter X binds to a receptor that opens a sodium channel then in this case the neurotransmitter is excitatory. If the same neurotransmitter binds to receptor that is coupled to a potassium channel (allowing an efflux) then the neurotransmitter is considered inhibitory in this case. A given vesicle contains only one type of neurotransmitter or peptide. But, a sysnaptic terminal may have several different vesicles which contain different neurotransmitters. As far as we know, if a neuron uses a given neurotransmitter or set of neurotransmitters at one of its synapses, it will use the same neurotransmitter or set at all of its synapses.