Chapter 2 - Cellular constituents of the brain

The brain consists of neurons and glia. While most of our discussion will consider functions of the neurons, there is growing recognition of the role of glial cells in maintaining critical functions of the brain. Therefore, we will need to say a few words about glia, as well.

The neuron

The primary building block of the nervous system is the neuron. Each neuron has a cell body, dendrites and one of more axons. The cell body, also called the soma or perikarion, contains the metabolic machinery and the genetic material for the neuron. Dentrites are the main site of synapse with other neurons, often at projections, called dendritic spines. The axon, beginning at the axon hillock, is the process that conveys the electrical signal from the neuron and it is often called the nerve fiber. Dendrites and axons usually have many branches and axo-dendritic synapses are the most common site of communication between neurons.

Resting membrane potential

The neuron maintains a resting membrane potential. This potential is based on the concentration gradient of ions that is created by an energy-dependent sodium-potassium ATPase pump. This pump moves 2 potassium ions into the neuron in exchange for 3 sodium ions moving out of the cell. Therefore, this pump directly creates a slight electrical potential, with the outside of the cell being slightly positive. The pump is said to be electrogenic. However, most of the resting membrane potential does not derive directly from this effect of the pump itself but rather from the force of the concentration gradient created by the pump. Because potassium is in high concentration inside the neuron, there is a concentration gradient attempting to force potassium out of the cell. Similar forces will attempt to move sodium ions into the neuron.

The membrane of the neuron is a lipid bilayer with embedded proteins. Some of these proteins are pumps (like the sodium-potassium ATPase pump) but many are ion channels. These ion channels are transmembrane proteins with a complex configuration that includes a pore through which ions can pass. Some channels permit constant passage of ions ("leak channels"), while some are opened by voltage change ("voltage-gated") or by chemical substances ("ligand-gated"). Most channels have selectivity, allowing only certain ions to pass when they are open. This selectivity is due to the particular conformation of the protein or the arrangement of charges in the ion pore.

The membrane at rest is semi-permeable with much higher permeability to potassium than to sodium (it contains potassium "leak channels"). Therefore, the potassium concentration gradient will force some positively charged potassium ions to escape from the cell. This is the primary generator of the voltage difference across the membrane, called the "resting membrane potential". This potential is usually somewhere between -70 and -90 millivolts, with the inside of the cell negative because positive potassium ions have left the cell. Of course, this potential would depend on the force exerted by the concentration gradient. As potassium leaves the neuron, the inside of the cell will become progressively more negative, which will attract the positive potassium ions, preventing further exodus. If this electrical force is great enough, it will actually draw potassium ions from the outside of the cell back inside.

Potassium ions will escape from the neuron until the electrical attractive force of the developing negative charge inside the cell equals the force exerted by the concentration gradient that is forcing potassium out. Be aware that it doesn't take the movement of many positively charged potassium ions to create a significant electrical force, so the overall concentration gradient does not change very much by this movement. At the point where inward and outward forces balance, the neuron is in equilibrium, with one potassium ion moving into the neuron for every one that leaves. The transmembrane voltage at which this balance occurs is called the "potassium equilibrium potential" and can be calculated from the Nernst equation (figure 1). This equation basically says that the equilibrium potential will be the product of a constant, multiplied by the natural logarithm of the ratios of concentration outside and inside the cell. A membrane potential can only be generated by ions that can actually cross the membrane. Since, in the case of neurons at rest, this is potassium, the potassium equilibrium potential nearly equals the measured resting membrane potential. However, it should be kept in mind that there is a very slight contribution to the membrane potential from movement of other ions. This contribution is proportional to their very low permeability. The Goldman-Hodgkin-Katz equation (figure 1) takes these other ions into consideration, although, if the permeability to an ion is very small relative to potassium, the ion can be basically ignored when considering the resting membrane potential. It is important to understand the resting membrane potential since this is necessary to understanding what happens when the neuron is excited.

Of course, all cells of the body have a resting membrane potential. This resting potential allows the cells to do work such as transporting molecules across their membranes. However, nerve and muscle cells are somewhat unique in that they have the property of being excitable. This excitability means that they can change their potential due to external chemical or mechanical factors.

Action potential

When we discuss electrical changes in the neuronal membrane this change is from the starting point of the resting membrane potential, where the inside of the cell is negative and the outside positive. Neurons at rest are considered to be "polarized," and "depolarization" makes the inside of the cell less negative and the outside less positive. "Hyperpolarization" is the opposite. Opening any ion channel will tend to bring the transmembrane voltage toward the equilibrium potential of whichever ions are permeable through that channel. For example, if a sodium channel were opened, the membrane potential would move toward the sodium equilibrium potential, with the inside of the cell being slightly positive relative to the outside. Again, this does not require the movement of very many positively charged ions into the cell and can occur quite rapidly when the channel is opened. The term "repolarization" is applied to the process of reestablishing the resting membrane potential after an event that depolarizes the cell.

Certain ion channels in the neuronal membrane are opened rapidly when the membrane potential reaches a particular voltage. These are termed voltage-gated channels. The particular voltage at which the channel opens is called the "threshold potential", at which point the conformation of the transmembrane proteins comprising the ion channel suddenly alter their conformation. The channel then becomes permeable to all of the ions conducted by that particular voltage-gated channel. Since many of these voltage-gated channels are permeable to sodium, which is in high concentration outside the neuron, there is rapid movement of a few sodium ions into the neuron that reverses the normally negative potential of the inside of the cell to a slight positivity. This rapid depolarization is termed an "action potential" (see figure 2).

The open voltage-gated sodium channels rapidly close, a process called inactivation. This terminates the depolarization or rising phase of the action potential. Additionally, voltage gated potassium channels open, which forces repolarization toward the potassium equilibrium potential by movement of potassium out of the cell. In fact, this produces slight hyperpolarization. During the brief period of sodium channel inactivation, these channels cannot be opened again and the membrane cannot be depolarized. This is termed the absolute refractory period. During the period of hyperpolarization that follows the action potential, it takes a large stimulus to generate another action potential and this is termed the relative refractory period.

An action potential produces a large change in voltage of a portion of the neuron. Because ions spread through the cytoplasm and the extracellular fluid, the action potential also depolarizes adjacent areas of membrane. This depolarization opens voltage-gated ion channels there and the action potential is regenerated at these adjacent sites. This action potential then spreads over the nerve cell and is regenerated in all areas where there are voltage-gated ion channels. This includes spread down the axon. Because the potential is regenerated at each level of the neuron, the action potential can extend the length of the axon and into all branches without decreasing in size. This is termed "propagation" of the action potential. Damage to an axon membrane or toxins that affect ion channels will affect the generation of the action potential or the conduction of the impulse.

The propagation of an action potential down an axon, with regeneration at each adjacent site is quite slow, usually less than a meter per second. This is a little faster in a larger diameter axon, but still quite slow. Myelination is a method for increasing the speed of conduction. Myelination is the process of wrapping layers of cell membrane tightly around the axon. This has the function of preventing ions from moving through these portions of the axonal membranes and also decreasing capacitance of the membrane by producing greater separation of the negative electrical charges inside from the positive charges outside the membrane.

In the central nervous system, the myelin sheath develops from oligodendroglial processes. In the peripheral nervous system, each segment of myelin is the result of wrapping of an individual cell, called a Schwann cell. There are gaps in between segments of myelin, the nodes of Ranvier. These are sites of high concentrations of voltage-gated ion channels. Because there is little movement of ions across the membrane where the myelin sheath is present, and because there is little charge concentration along the membrane in the internodal segment (due to low capacitance), ions can move relatively freely down the axon. This produces sufficient depolarization at the next node of Ranvier without having to regenerate the action potential at each successive part of the axon. This markedly increases the speed of conduction of the axon, with the distance between nodes being directly proportional to the amount of the velocity increase. Damage to myelin significantly slows or can even block axonal conduction. The largest motor axons are those that connect the nervous system to skeletal muscle and they conduct between 50 and 100 plus meters/second. Autonomic postganglionic motor axons to glands, organs and blood vessels are unmyelinated and conduct very slowly (usually less than 1 meter per second). Touch, pressure and muscle stretch sensation are conducted by large, myelinated fibers and pain and temperature sensation by small myelinated or unmyelinated sensory fibers.

The synapse

Most axons terminate in a "synapse" on the dendrites of other neurons, often on small dendritic spines. The synapse is the site of transmission between neurons. While there are rare gap junction-type synapses in which there is actual flow of ions between neurons, the vast majority of synapses are "chemical synapses". These involve the release of neurotransmitter by the axon terminal when an action potential reaches it. The axon terminal contains vesicles or "quanta" of neurotransmitter and release of transmitter from synaptic vesicles occurs by a multi-step process. The action potential opens voltage-gated calcium channels on the nerve terminal, resulting in an inflow of calcium because calcium is in higher concentration outside of cells. The calcium in the nerve terminal results in a series of chemical interactions between proteins in the nerve terminal that ultimately result in vesicles of neurotransmitter mobilizing, binding and then fusing to the axonal presynaptic membrane. This fusion results in release of the content into the synaptic cleft. Some nerve terminals will release the contents of hundreds of vesicles every time an action potential reaches the nerve terminal. This is true of the neuromuscular junction. Some nerve terminals will release only one vesicle with a depolarization. This happens at many central nervous system axon terminals. In some synapses, only every second or third action potential actually results in the release of a vesicle of neurotransmitter.

The neurotransmitter diffuses across the "synaptic cleft" to the postsynaptic side (usually on a dendrite), where the transmitter binds with specific receptors. Many of these receptors are part of an ion channel called a "ligand-gated" ion channel. These ion channels have very specific permeability to particular ions. Depending on the particular ion permeability of the channels, the receptor may excite or inhibit the postsynaptic neuron. There are other receptors that are not ion channels. These receptors, termed "second messenger receptors," are linked to internal processes within the postsynaptic neuron, such as enzymes that can change the function of the neuron. Many of these are linked to g-proteins which can increase the intracellular concentration of compounds such as cyclic AMP, inositol triphosphate or diacyl glycerol. Since these receptors frequently do not directly affect the membrane potential they are often described as being modulatory, and the transmitters that bind to these receptors are often termed "neuromodulators". Because they can change many functions within the cell, their effects can be very long-lasting.

The effect of neurotransmitter is terminated by one of a few mechanisms. There may be enzymes that break down the neurotransmitter, such as the effect of acetylcholinesterase on acetylcholine. Blockade of acetylcholinesterase by drugs or toxins will prolong the effect of acetylcholine release. Another possibility is that the transmitter may diffuse away from the synaptic cleft, usually to be taken up by glial cells around the area. A third possibility is that the transmitter may be taken back up into the nerve terminal through specific transport mechanisms. In this case the transmitter may be repackaged for later release. Drugs such as the selective serotonin reuptake inhibitors affect this process.

In the case of ligand-gated ion channel-type receptor, the effect of opening the channel depends on the particular ions that can pass through it. In every case, opening these channels will tend to drive the membrane potential toward the equilibrium potential for the ions to which it is permeable. This has been termed the "reversal potential" for the receptor. If this reversal potential is at a level that would result in the membrane reaching threshold it is termed an excitatory receptor since, if enough of these channels are opened, an action potential will be generated. For example, any ligand-gated receptor that is primarily permeable to sodium or calcium would be excitatory. If the reversal potential for a receptor is at a level that would not reach threshold, it would be an inhibitory receptor. Opening this type of channel would prevent the neuron from reaching threshold and therefore prevent it from generating an action potential. For example, opening a receptor that was permeable to potassium would be inhibitory.

One concept that is difficult to grasp initially, is that a transmitter may result in sight membrane depolarization, but still be an inhibitory receptor. This would occur if the reversal potential for the receptor was more positive than the resting membrane potential but still more negative than threshold for the neuron. While opening this type of receptor would slightly depolarize the neuron, it would tend to hold the neuron at this potential and resist further depolarization toward threshold. Therefore, it is an inhibitor of action potential generation. This is the case with the opening of chloride channels in the adult nervous system. The most common inhibitory receptor in the brain is the GABAA receptor that binds gamma amino butyric acid and is permeable to chloride. This receptor is particularly important since many inhibitory drugs modulate the activity of this receptor, including alcohol, benzodiazepines and barbiturates.

If the cumulative activity of thousands of synapses brings the neuron to threshold through a process of summation, an action potential is generated and the process of transmission of the nerve impulse is begun once again. There are very few voltage-gated channels on the dendrites, and therefore, action potentials usually don't begin there. Voltage-gated channels are clustered in the axon hillock region at the beginning of the axon, which is the typical site of action potential generation. Depolarization of dendrites must spread to the axon hillock in order to summate into an action potential. Because the effect of this depolarization has to spread out over the neuron, it becomes smaller and smaller the further it has to travel. This is termed "electrotonic spread" of depolarization and means that a synapse located further out on a dendrite is going to produce less change at the axon hillock than would a similar synapse close to the soma.

Glia

Glial cells are important in the brain. We have already seen how oligodendrocytes comprise central nervous system myelin. Astrocytes surround neurons and blood vessels. These are responsible for the critical function of maintaining the normal ionic and nutritive environment around neurons. They remove ions and transmitters that accumulate due to neuronal activity and make sure the extracellular environment is ideal for the neuron. They release growth factors and cytokines that are important for neuron health. Finally, they stimulate the brain capillaries to develop tight junctions and other specializations of endothelial cells that contribute to the blood-brain barrier (see section XIIb).

Ependymal cells are a type of glial cell that lines the ventricular system. These cells do not provide a barrier between the cerebrospinal fluid and the brain. Therefore, substances delivered to the CSF have direct access to the brain and spinal cord.

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