Unit II: Neurons and neurotransmission

 

Some definitions:

 

Action potential: A self-propagating electrochemical impulse. The chain reaction of events that involves the temporary loss or reversal of polarization at a segment of the axon and initiates the same repeating sequence of events in the immediately adjacent portion of the axon ultimately resulting in neurotransmitter release form the nerve terminal.

 

Axon and terminal: The transmitting neurofilaments of neurons. Electrochemical impulses called action potentials travel down the axon resulting in the release of neurotransmitters from the terminal area where they are stored in discrete packages called vesicles. The axon terminals are small knob-like swellings sometimes referred to as boutons from the French for "button." The terminal is synonymous with the presynaptic membrane.

 

Dendrites: The receptive neurofilaments of neurons containing receptors where neurotransmitters bind. Also referred to as the postsynaptic membrane.

 

EPSP: Excitatory postsynaptic potential. A depolarizing stimulus that increases the likelihood that the receiving neuron will "fire" or initiate an action potential.

 

Gray matter: That portion of the brain that appears gray. The color reflects the absence of myelination (which makes the tissue appear white). The gray matter consists of the cell bodies, dendrites, and unmyelinated axons that comprise the nervous system's microcircuitry.

 

IPSP: Inhibitory postsynaptic potential. A stimulus that decreases the likelihood that the receiving neuron will fire, usually by hyperpolarizing it.

 

Neurofilaments: Fine threadlike structures called dendrites and axons that are special adaptations and unique features of neurons that enable them to send and receive electrochemical signals.

 

Neuroglia: Literally "nerve glue." The central nervous system consists of neurons and glial cells. Neurons constitue about half the volume of the CNS and glial cells make up the rest. Neurons transmit information, but glial cells do not. Glial cells provide support and protection for neurons (physically and nutritionally). They are thus known as the "supporting cells" of the nervous system. The four main functions of glial cells are: to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy and remove the carcasses of dead neurons (clean up). The three types of CNS supporting cells are 1) astrocytes, which are relatively large, star-shaped cells that connect neurons with the brain's blood supply and also anchor neurons in place; 2) Oligodendrocytes (oligodendroglia) which function principally to encase axons in insulating sheaths called myelin which increases the rate at which they can conduct impulses and 3) Microglia, which help clean up CNS debris. Microglia protect the brain from invading microorganisms and are thought to be similar in nature to microphages in the blood system. The supporting cells of the PNS are known as Schwann Cells.

 

Neuron: A nerve cell that receives, integrates and transmits electrochemical signals; the functional units of the nervous system.

 

Neurotransmitter: A chemical messenger that carries information from one neuron to another at the synapse. (Actually, auto-transmission can also occur. This is when a single neuron synapses with itself.) There are three general categories of neurotransmitters: (1) monoamines like serotonin, norepinephrine, dopamine, and acetylcholine (the term amine simply refers to any organic molecule containing a nitrogen atom derived from ammonia NH3); (2) amino acids like GABA and glutamate; and (3) neuropeptides or small proteins like beta-endorphin and Substance P.

 

Polarization: The state of having opposite qualities or powers. The difference in electrochemical charge that develops between the outside and inside of the neural membrane such that the interior is negatively charged relative to the exterior. For all intents and purposes, polarization is synonymous with a neuron's resting membrane potential (e.g., it is not firing).

 

Receptors: Specialized molecular binding sites where neurotransmitters dock thereby producing physiologic effects. Most receptors are large proteins that span the neural membrane thus having portions on the exterior of the cell where the neurotransmitters bind, and portions in the cell's interior that subsequently initiate biochemical reactions within the neuron.

 

Resting potential: The difference in voltage across a neuronal membrane when the neuron is not firing.

 

Reuptake: A mechanism by which a neurotransmitter is pumped or vacuumed back into the presynaptic terminal that released it.

 

Soma: The cell body containing the nucleus and many other cytoplasmic organelles (little organs of the cell) and the point of origin of the neurofilaments, the dendrites and axon.

 

Synapse: The junction between neurons transmitting and receiving membranes. Usually a physical gap across which neurotransmitters diffuse when released.

 

TOE: Threshold of excitation. A critical degree of excitation or depolarization at which the neuron initiates an action potential or fires in an all-or-none fashion.

 

White matter: Whitish appearing patches and paths in the brain composed of myelinated axons.

 

 

Neural Transmission: The Language of Chemical Communication

 

Neurons, also referred to as nerve cells, are the functional units of the nervous system. Essentially, neurons receive, integrate, and transmit electrochemical impulses via neurotransmitter-dependent, ionic and/or enzymatic interactions across cellular membranes. Like all nucleated animal cells (i.e., cells having a nucleus or eukaryotes) neurons have the typical complement of organelles, but have in addition some unique features that make them especially well adapted to their roles as signal senders and receivers. These unique characteristics are neurofilaments called dendrites and axons.

 

Although it is a slight oversimplification, dendrites can be thought of as the neuron's receptive membrane or the site where most incoming messages are received. A given neuron can have many points on its soma where dendrites originate. Axons, the neuron's transmitting components, are the structures that send signals. While both dendrites and axons may branch out into numerous offshoots, usually the axon originates from a single trunk called the axon hillock where it leaves the cell body. Most neurons synthesize their neurotransmitters in their cell bodies, package them in membranous sacks called vesicles (which protect the neurotransmitter from enzymatic degradation), and store them in their axon terminals where they await release upon the arrival of an action potential in order to be released. Neurons that release monoamine neurotransmitters also have the capacity of synthesizing neurotransmitters at the presynaptic terminals.

 

When a neuron is at rest (i.e., not "firing" or sending an impulse) a very narrow margin of the axon's interior is negatively charged. Conversely, a very narrow margin of the exterior fluid surrounding the outer membrane of the axon is positively charged. This separation of charge, so that the interior of the neuron is negatively charged relative to its exterior, is termed polarization (the state of having opposite qualities or powers). Polarization is due to a property of the cellular membrane called selective permeability which means that the membrane allows some molecules to cross into or out of the cell, but not others. Another important factor that helps to polarize the neuron is an active (energy-requiring), membrane-bound, molecular pump that extrudes sodium ions and retrieves potassium ions. Since the pump has binding sites of three sodium atoms, but only two for potassium atoms, for every three sodium ions pumped out of the cell, only two potassium ions are taken in. Because the resting neural membrane is normally impermeable to sodium, a large concentration gradient develops so that the quantity of sodium ions outside the neuron is much greater than the quantity of sodium within it. Since substances tend to seek equilibrium by moving down concentration gradients (i.e., molecules will randomly move by diffusion from areas of high concentration to areas of lower concentration) a significant tension builds, tending to force the sodium into the cell. Similarly, inside the cell's axon a concentration gradient develops that favors the movement of potassium ions out of the neuron. The net result is that the immediate interior of the neuron is negatively charged relative to the immediate exterior. This charge difference, of about 70 millivolts, is called the neuron's resting membrane potential and can be thought of as analogous to a cocked crossbow.

 

When the TOE is exceeded, the crossbow will fire by suddenly releasing the energy stored in its bow. Similarly, since the sodium and potassium ions are seeking to equalize their distribution across the axon's membrane (they are "cocked") if anything occurs to increase the permeability of the membrane to them, an immediate rush of sodium into and potassium out of the cell will result.. This flip-flop of ions - sodium in, potassium out - causes a change in the neuron's polarity so that its interior becomes momentarily positive relative to its exterior, and the neuron is said to have depolarized.

 

Certain neurotransmitter-receptor interactions increase membrane permeability to sodium ions which produces a decrease in the degree of polarization (partial depolarization) because the interior membrane margin becomes less negatively charged due to the influx of positively charged sodium ions. This is referred to as an EPSP, or excitatory postsynaptic potential, and tends to push the neuron toward firing. Other neurotransmitter-receptor interactions produce an increase in the degree of polarization (hyperpolarization) either because of increasing membrane permeability to negative ions like chloride, thus adding additional negative molecules to the already negative intracellular environment, or by further decreasing permeability to positive ions (so that even more accumulate outside the membrane). This is called an IPSP, or inhibitory postsynaptic potential, which tends to inhibit the neuron from firing.

 

At any moment, a neuron can be receiving dozens, perhaps even hundreds or thousands, of signals from many other neurons. Some can be EPSPs while others might be IPSPs. When the amount of excitation from EPSPs crosses a threshold, the threshold of excitation or TOE, the neuron fires. The process works as follows. In a nerve cell that is "at rest," positively charged Na+ (sodium) ions are kept outside the cell, whereas positively charged K+ (potassium) and negatively charged Cl- (chlorine) ions can pass into the cell. Thus the environment inside the cell is electrically more negative than the environment outside the cell. In this polarized state the cell has potential energy that can be released by a stimulus to the cell membrane.

 

A stimulus that is of sufficient intensity causes sodium gates in the membrane to open, allowing positively charged Na+ ions to rush into the cell. This causes a reverse in the cell's electrical polarity, so that the environment inside the cell now is more positive than the environment outside the cell. After the cell reaches its maximally positive state, its sodium gates close and its potassium gates open to allow the positively charged potassium ions (K+) to leave the cell. The environment inside the cell once again becomes more negative than the environment outside the cell. At this point, the sodium-potassium pump removes sodium ions and retrieves potassium ions thus restoring the membrane's resting potential. This complete sequence of events is termed the action potential and is initiated at the axon hillock; the conical area of origin of the axon from the nerve cell body.

 

The occurrence of the action potential at any given point along the axon triggers a similar succession of changes in the immediately adjacent portion of the axon. And as the sequence is replicated there, a similar series of events arises in the next axonal segment and so on down the line. In this manner, the action potential is self-propagated like a wave along the entire length of the axon. Most neurons, however, have myelin sheaths covering most of their axons like insulation around an electric cord. The myelin sheaths surrounding axons have discrete segments called nodes where the axon's membrane is unsheathed. This allows the action potential to jump from node to node, rather than traversing along the entire length of the axon, thus increasing the speed that nerve signals can travel. For example, some large myelinated nerve fibers, such as those supplying skeletal muscles, conduct impulses as fast as 120 meters per second (360 miles per hour), compared with speeds of only a few millimeters per second (2 miles per hour) in small, unmyelinated fibers like those supplying the digestive tract. Note that the process within the neuron axon involves electrical conduction.

 

When the action potential reaches the terminal portions of the axon, a cascade of events takes place that results in the release of neurotransmitters into the synaptic space - a process called exocytosis. Basically, when the action potential reaches the terminal button, calcium channels are opened. As calcium flows into the presyntaptic neuron, it anchors the vesicles holding the neurotransmitters onto the membrane so that the chemicals can be released onto the synapse. Note that communication between neurons involves a chemical process. Once released the neurotransmitter diffuses across the synapse where some of it binds to specific molecular receptors on the postsynaptic membrane. Depending on the type of neurotransmitter and the nature of the receptor, the neurotransmitter-receptor interaction will produce either an EPSP or an IPSP. When the sum of the EPSPs and IPSPs exceeds the TOE, the postsynaptic neuron will fire. This entire process is called neural transmission and the communication between neurons is called the first messenger system.

 

In addition to regulating ion channels in the cellular membrane, many neurotransmitter-receptor interactions activate second-messenger systems. Briefly, the second-messenger systems involve complex biological reactions that take place in the cell's interior. The neurotransmitter as the first messenger activates or inhibits other chemicals inside the cell that then also function as chemical messengers. These second-messengers, in turn, initiate a variety of physiologic events, usually involving activation of specific enzymes, that produce additional (third) chemical messengers and biochemical reactions that can ultimately influence the genetic functions of the cell. It is through these second-messenger mediated intracellular process that most psychotropic medications are believed to exert their therapeutic effects.

 

Neurotransmitters

Currently there are three major types of neurotransmitters that can be classified according to their chemical composition or molecular structure: the monoamines, amino acids, and neuropeptides. A commonly asked question is if a given neurotransmitter is excitatory or inhibitory. The answer is "it depends." While some transmitters are typically described as inhibitory (e.g., GABA) and others as excitatory (e.g., norepinephrine), whether or not a given neurotransmitter produces an IPSP or an EPSP depends on the receptor it binds to. Most transmitters bind to several subtypes of receptors, not just one. For example, there are at least seven varieties of serotonin receptors, five kinds of dopamine receptors, and at least 3 receptors for norepinephrine. At some receptors.  norepinephrine is excitatory (e.g., at most of its targets in the sympathetic nervous system) while at others it is inhibitory (e.g., at alpha-2 receptors in the locus ceruleus, a brain stem structure implicated in acute anxiety and panic). Thus, there are probably no absolutely excitatory nor invariably inhibitory neurotransmitters. Postsynaptic potentials always depend on the specific transmitter-receptor interaction. Furthermore, many neurotransmitters are found all through the body, not only in the CNS, and play many different roles at these peripheral locations (e.g., serotonin is widely distributed throughout the gut and on the surface of red blood cells).

Some neurotransmission is very fast in onset (within millseconds). For example, two fast-onset neurotransmitters are GABA (which is primarily inhibitory), and Glutamate, which is primarily an excitatory neurotransmitter. Some neurotransmitters are slow acting (up to two seconds after binding at the post-receptor site). These include some of the monamine neurotransmitters and some of the neuropeptides. These slow acting NT are sometimes referred to as neuromodulators because they can influence the effects of future neurotransmissions at the same post-synaptic site(s). In some cases, these effects can last for a few days.

 

The most well known small molecule neurotransmitters are the monoamines which consist of a variety of chemicals including serotonin, norepinephrine, epinephrine, dopamine, acetylcholine, and histamine. Serotonin has many important functions in the CNS and is thought by some to be the "work horse" of neurotransmitters. It is involved in sleep, arousal, motivation, appetite, and sex. Norepinephrine plays a "Paul Revere" role in the brain in that it sounds the alarms that mobilize our fight-or-flight stress response. Both serotonin and norepinephrine appear to be involved in depressive illnesses. Norepinephrine's chemical cousin, epinephrine, is not well understood as a neurotransmitter, but it appears to be involved in regulating some autonomic (life support) processes. Dopamine is critically important in mediating extrapyramidal motor control and when deficient results in symptoms of Parkinson's disease. It is also involved in regulating the release of some important pituitary hormones, and is clearly related to psychotic disorders like schizophrenia, some drug addictions, and the brain’s reward system.  Acetylcholine's role in the CNS seems related to learning and memory. Alzheimer's disease, a progressive neurodegenerative illness whose hallmark is memory loss, appears to involve the degeneration of the brains major acetylcholine producing structure, the hippocampus. Histamine's function in the brain is not well understood.

 

The amino acid neurotransmitters that have been extensively studied are the predominantly inhibitory transmitters GABA (gamma-aminobutyric acid) and glycine; and glutamate and aspartate which both appear to be predominantly excitatory. In addition to monoamines and amino acids, the brain contains an unknown number of peptide (small protein) neurotransmitters called neuropeptides. Two of the most well studied neuropeptides are beta-endorphin, which is a naturally occurring opiate-like molecule, and substance P which appears to be important in conveying pain sensations and is now under investigation for it's suspected role in depression. Many of the peptide transmitters are believed to act as neuromodulators or neuroregulators by modulating or regulating the binding of other transmitters like the monoamines and amino acids at their receptors. They are also thought to exert longer lasting postsynaptic influences than monoamine and amino acid transmitters.

 

By far the most well studied neurotransmitters are the monoamine transmitters, especially acetylcholine and norepinephrine since they occur in high concentrations in the peripheral nervous system and are, therefore, more accessible and more easily segregated than centrally located transmitters. The monoamines collectively account for only 5 to 10 percent of the synapses in the human brain whereas the amino acid transmitters account for up to 60 percent of CNS synapses. While only a handful of neurotransmitters have been confidently classified to date, it is believed that as many as several hundred yet to be identified neurotransmitters exist. To make matters still more complex, it is now know that most neurons have co-localized neurotransmitters (that is, a single neuron may produce and release more than one neurotransmitter). In fact, it appears that a given neuron can release as many as three different neurotransmitters simultaneously; usually one of each of the three major types - a monoamine along with an amino acid and a neuropeptide.

 

To complicate things even further, there are numerous permutations of synaptic connections (Hyman & Nestler, 1993). Most synapses are axodendritic, i.e., the axon of one neuron synapses with the dendrite of another. But there are also axosomatic (axon to cell body), and axoaxonic (one neuron's axon synapses with another neuron's axon) synapses. In addition, dendrites may also synapse with each other in dendro-dendritic connections. And to introduce yet another layer of complexity, not all neurons communicate at chemical synapses. Some neurons interconnect at what are described as electrical synapses.

 

Neurons in and of themselves are not especially smart. As we have described, they can do very few things, such as fire or not fire, and communicate with a relatively limited vocabulary of only a few types of chemicals. But, put one hundred billion of them together in a small area, and let each one "speak" with thousands of other neurons in very specific and precise ways, and a literal brainstorm of activity will take place resulting in the infinite diversity of human conscious experience.

 

 

Brief Description of the Action Potential

 

As we have discussed, neurons send messages through an electrochemical process. Chemicals in the body that have an electrical charge are called "ions." The important ions in the nervous system are sodium and potassium (both have 1 positive charge, +), calcium (has 2 positive charges, ++) and chloride (has a negative charge, -). There are also some negatively charged protein molecules inside of the cell. Recall that nerve cells are surrounded by a membrane that allows some ions to pass through and which also blocks the passage of other ions. This type of membrane is called semi-permeable.

 

Resting Membrane Potential

 

When a neuron is not sending a signal, it is said to be "at rest." When a neuron is at rest, the inside of the neuron is negatively charged relative to the outside. If you measure the difference in the voltage between the inside and outside of the neuron, you have the resting potential. The resting membrane potential of a neuron is about -70 mV (mV=millivolt) - this means that the inside of the neuron is 70 mV less than the outside.

 

Note that the measurement of voltage is always relative - comparing two regions to each other. If one compares the region with more positive charges to a region with more negative charges one has a positive voltage. If you compare a region with more negative charges to a region with more positive charges, the voltage is negative. Thus in the axon, there are more negative charges on the inside than on the outside during the resting potential, giving the axon a negative voltage when comparing the inside to the outside

 

Although the concentrations of the different ions attempt to balance out on both sides of the membrane, they cannot because the cell membrane allows only some ions to pass through channels (ion channels). At rest, potassium ions (K+) can cross through the membrane easily, but (at rest,) chloride ions (Cl-) and sodium ions (Na+) have a more difficult time crossing. The negatively charged protein molecules inside the neuron cannot cross the membrane.

 

In addition to these selective ion channels, there is a pump that uses energy to move 3 sodium ions out of the neuron for every 2 potassium ions it puts in. (the sodium/potassium ATPase). This activity results in a net loss of positive charges within the cell. In addition, some potassium channels in the plasma membrane are "leaky" allowing a slow diffusion of K+ out of the cell (which also results in a net loss of positive charges). At rest, the concentration of Na+ outside the cell is about10 times greater than that inside the cell. Also, the concentration of K+ inside the cell is about 20 times greater than that outside the cell.

 

Action Potential

 

The resting potential indicates what is happening with the neuron at rest. The action potential indicates what happens when the neuron transmits information down an axon, away from the cell body, and fires. Neuroscientists use other words, such as a "spike" or an "impulse" to describe the action potential. The action potential is an explosion of electrical activity that is created by a depolarizing current. This means that some event (a stimulus) causes the resting potential to move toward 0 mV. When the depolarization reaches about -55 mV a neuron will fire an action potential. This is the threshold of excitation (TOE). If the neuron does not reach this critical threshold level, then no action potential will fire. However, when the TOE level is reached, an action potential of a fixed sized will always fire. In any given neuron, the size of the action potential is always the same. There are no big or small action potentials and all action potentials are the same size. Therefore, the neuron either does not reach the threshold or a complete action potential is fired - this is the "ALL OR NONE" principle.

 

The "cause" of the action potential is an exchange of ions across the neuron membrane. A stimulus first results in the opening of sodium channels. Because there are a lot more sodium ions on the outside, and the inside of the neuron is negative relative to the outside (opposite charges attract each other), sodium ions rush into the neuron. Sodium has a positive charge, so the neuron becomes momentarily more positive (on the inside) and becomes depolarized. The sudden complete depolarization of the membrane opens up more of the voltage-gated sodium channels in adjacent portions of the membrane. In this way, a wave of depolarization sweeps along the cell. This is the action potential, which is also called the nerve impulse. In myelinated neurons , the action potenial jumps from unmyelinated node to node in order to speed up transmission. The voltage-gated sodium channels of myelinated neurons are confined to these spots (called nodes of Ranvier).

 

When the inside of the axon becomes sufficiently positive, about 30 mV is given as an average value, the sodium channels close. In addition to the sodium channels closing, the potassium (K+) channels open, but it takes longer for potassium channels to open. When they do open, potassium rushes out of the cell, reversing the depolarization.. This causes the action potential to go back toward -70 mV (a repolarization). The action potential actually goes past -70 mV (a hyperpolarization) because the potassium channels stay open a bit too long. Gradually, the ion concentrations go back to resting levels and the cell returns to -70 mV. Until the 70 mv polarity is reestablished, the neuron will not be able to fire again. This is called the refractory period and lasts about ,.001 seconds. However, on the average, an excited neuron can fire about 500 to 1000 times in one second.

 

Some neurotransmitters inhibit the transmission of nerve impulses (IPSP). They do this by opening

 

1) chloride channels (letting negatively-charged chloride ions (Cl-) IN and

2) potassium channels in the plasma membrane (positively-charged potassium ions (K+) OUT

 

Although the threshold voltage of the cell is unchanged, it now requires a stronger excitatory stimulus to reach threshold.

 

For example, gamma amino butyric acid (GABA). This neurotransmitter inhibits nerve transmission by both mechanisms:

 

1) binding to GABAA receptors opens chloride channels in the neuron.

2) binding to GABAB receptors opens potassium channels.

 

Role of the axon hillock

A single neuron may have thousands of other neurons synapsing on it. Some of these release activating (depolarizing) neurotransmitters; others release inhibitory (hyperpolarizing) neurotransmitters. The receiving cell is able to integrate these signals.

 

Note that:

 

1. The EPSP created by a single excitatory synapse is insufficient to reach the threshold of the neuron.

2. EPSPs created in quick succession, however, add together ("summation"). If they reach threshold, an action potential is generated.

3. The EPSPs created by separate excitatory synapses can also be added together to reach threshold.

4. Activation of inhibitory synapses makes the resting potential of the neuron more negative. The resulting IPSP may prevent what would otherwise have been effective EPSPs from triggering an action potential.

 

The action potential is usually generated in the axon hillock. Having neither excitatory nor inhibitory synapses of its own, it is able to evaluate the total picture of EPSPs and IPSPs created in the dendrites and cell body.

 

Only if, over a brief interval, the sum of depolarizing signals minus the sum of the hyperpolarizing signals exceeds the threshold of the axon hillock will an action potential be generated. In most neurons, this process occurs very rapidly (e.g., under a second).