Nervous Tissue

The Neuron

Neurons relay and integrate information between two distal sites. Neurons can connect two cells and transmit information from one cell to the other or they can sense the external environment and deliver that information to another cell.

Information is relayed by electrical impulses that are triggered at the ends of dendrites. These impulses represent depolarization of the cell membrane during which usually sodium ions enter the cell to make the membrane potential more positive. These impulses propagate down dendrites toward the cell body, and then potentially continue down the axon to the axon terminus where the signal is delivered to another cell.

Information transfer

Information is relayed by electrical impulses that are triggered at the ends of dendrites. These impulses represent depolarization of the cell membrane during which usually sodium ions enter the cell to make the membrane potential more positive. These impulses propagate down dendrites toward the cell body, and then potentially continue down the axon to the axon terminus where the signal is delivered to another cell.

Whether an impulse that starts in the dendrite will continue down the axon depends upon the strength of the impulse as it reaches the initial segment of the axon. This segment is called the axon hillock and it receives both stimulatory and inhibitory signals. If the sum of those signal is of sufficient strength, then an action potential is triggered and travels down the rest of the axon.

As impulses move down the dendrite, they lose their strength. If the impulses have sufficient strength when they reach the axon hillock, they can trigger an action potential in the axon. In many neurons, a single impulse is not sufficient to trigger the initiation of an action potential; rather several impulses must be summed at the axon hillock. These impulses could come from inputs at the branches of the dendritic tree or from impulses at one location triggered in rapid succession.

Synapses

If an action potential is triggered in the axon, it travels down the length of the axon to its terminus. The axon terminus forms a synapse on the target cell to mediate communication between the axon and the target cell. There are two classes of synapses: electrical and chemical. Electrical synapses use gap junctions to pass information from the axon to the target cell. For example, the sodium ions that enter the axon during the action potential can pass through gap junctions to the target cell. In addition, an increase in an other cytosolic ion can also pass to the target cell. One advantage of electrical synapses is their speed compared to chemical synapses, but they lack the ability to increase the gain of the signal.

Chemical synapses consist of the release of a neurotransmitter from the axon that binds a receptor on the surface of the target cell. Neurotransmitters are stored in synaptic vesicles in the terminus of the axon. An action potential triggers the fusion of some of these synaptic vesicles with the cell membrane to release the stored neurotransmitter. The neurotransmitter associates with receptors on the surface of the target cell. Binding to the neurotransmitter initiates a signaling pathway that alters the behavior of the target cell.

Types

Neurons can adopt a variety of architectures. A bipolar neuron contains a single axon and dendrite. The ends of the dendrite and axon may branch but there is only one connection of each to the cell body. The strength of the signal traveling down the single dendrite determines whether an action potential is triggered in the axon.

Multipolar neurons contain a single axon but extend several dendrites from the cell body. This allows them to integrate inputs from several different sources and the strength of the signal arriving at the axon hillock is summation of the signals coming from each dendrite.

A third type of neuron is pseudounipolar. These neurons contain a single extension from their cell bodies. The extension splits and extends axons in opposite directions. The advantage of a pseudo unipolar neuron is that they don’t show the same attenuation of signal from the input seen in dendrites of bipolar and multipolar neurons because they lack a dendrite and have only a single axon. Therefore, a stimulus in the dendrites that depolarizes the membrane is likely to generate an action potential that reaches the axon terminus. Many sensory neurons are pseudounipolar.

Schwann Cell and Myelin

Most peripheral neurons have cells that associate with their axons called Schwann cells. Cells in the central nervous system have similar cells called oligodendrocytes which will be described in Connection to the World. Schwann cells provide metabolic and structural support to the neuron and in some cases wrap an axon in layers of myelin. Myelin forms when Schwann cells extend a portion of their cell membranes and cytoplasm around the axon and then repeated wrapping by the Schwann cell create a structure with several layers of Schwann cell membrane and cytoplasm. As seen in the electron micrograph, myelin forms a thick layer of Schwann cell membrane and cytoplasm that separates the cell membrane of the axon from the interstitial fluid. Myelin plays an important role in how action potentials propagate down axons.

Several proteins in the Schwann cell membrane interact to compact and extrude the cytoplasm from the portion of the Schwann cell that forms myelin around an axon. One critical protein in this process is myelin basic protein. Mutations in the genes that encode these proteins can compromise the structure of myelin leading to loss of neuron function and neurological disorders.

The section of the cell membrane in Schwann Cells that makes myelin requires a unique set of lipids. Some of the lipids that are prominent in myelin are galactoceramides, gangliosides and plasmalogens, which are shown below. The exact roles of the lipids in myelin is still being investigated, but they likely play a role in generating the compactness of cell membrane and signaling events to maintain the integrity of myelin.

A single Schwann cell wraps only a small section of an axon and many Schwann cells line up along the axon to envelope it in myelin. The only gaps in myelin are between adjacent cells where a section of the axon is not wrapped in myelin. These gaps are called nodes of Ranvier and contain high concentrations of voltage-gated sodium channels. These channels open when membrane potential depolarizes (becomes more positive). The opening of the channels further depolarizes the membrane to maintain the strength of the action potential. Where myelin wraps the axon the membrane capacitance is low, so the current that entered the axon at the node passes rapidly through the cytoplasm to the next node to trigger opening of voltage-gated sodium channels and depolarization of the membrane. Thus, action potentials travel down axons by hopping from node to node which is much faster in most neurons.

Schwann cells also associate with axons in the periphery without wrapping them in myelin. These are called unmyelinated axons. Note the Schwann cell surrounds the axon but does develop the many layers of myelin. A Schwann cell that does myelinate axons can associate with and support multiple axons.

The advantage of myelination is that it increases the rate of conductance down the axon. The rate of conductance down an axon is related to the diameter of the axon with large axon able to generate faster rates of conductance. A myelinated axon shows a significant increase in conduction velocity compared to an unmyelinated axon. Myelination increases the rate because the depolarization hops from node to node.

Axonal Transport

Axons can be very long (up to 1 m in some people) and the proper functioning of axons depends upon delivery of material, such as mitochondria and synaptic vesicles, from the cell bodies and the return of organelles from the axon terminus to the cell body. The rates of diffusion for proteins and organelles are too slow to support the needs of neurons, so cells must expend energy to move material up and down axons. The chart shows the approximate time it would take a protein or organelle to diffuse from the cell body to the end of an axon of a particular length. Note that diffusion is too slow to account for the distribution of material in most neurons.

Neurons can move material down axons by two different mechanisms: fast transport and slow transport. Using fast transport, neurons can move synaptic vesicles from the cell body down the axon (anterograde) at rates of 200 - 400 mm/day. They can also move organelles in the opposite direction (retrograde) at similar rates. There are some organelles, such as mitochondria, which show bi-directional transport. These may move a short distance in one direction and then reverse directions. In slow transport, certain cytosolic proteins, mostly those that compose the cytoskeleton, move down the axon but at much slower rates.

Kinesin and dynein are responsible for generating fast transport of material in the anterograde and retrograde directions, respectively. Neurons organize microtubules in axons with the plus ends oriented towards the the axon terminus and minus ends pointing to the cell body. Because kinesis and dynein move in opposite directions along microtubules, neurons use kinesin to deliver material from the cell body to the axon terminus and dynein to return material from the axon terminus to the cell body. These motors also move material during slow axonal transport which is slower because the motor pauses often during transport.

Nerve Damage and Repair

Peripheral nerves contain axons that relay information between the spinal cord and different sites in the body. Peripheral nerves are often very long and need both mechanical and metabolic support. Peripheral nerves are also prone to damage due to trauma incurred at distal sites in the body.

Connective Tissue Layers

Peripheral nerves contain axons from several neurons and contain three layers of connective tissue. Connective tissue contains extracellular matrix and specific cells which we will describe in greater detail in the TBL on connective tissue. Each axon in a peripheral nerve is associated with a Schwann cell that may or may not wrap the axon in myelin. The Schwann cells and surrounding extracellular matrix make up the endoneurium. Several axons are bundled into a structure called a fascicle. Each fascicle is wrapped by another layer of connective tissue called perineurium. Finally, the entire nerve is wrapped in a layer of connective tissue called the epineurium. Note that blood vessels are not found in the perineurium but not the endoneurium.

Degrees of Nerve Damage

The severity of damage to a nerve is based on how extensively the axon and connective tissue layers are damaged. Nerve damage is classified based on the extent of damage to axons and connective tissue layers. Below are listed classes in order from mildest to most severe.

• Grade I: segmented demyelination, thinner myelin layer
• Grade II: Axon damage with intact endonuerium
• Grade III: Axon and endoneurium damaged with intact epineurium
• Grade IV: Axon, endoneurium and perineurium damaged with intact epineurium
• Grade V: complete nerve transaction

Response to Nerve Injury

When a nerve is damage that includes damage to the axon, the initial response is to send a signal from the point of damage back to the cell body to trigger expression of genes that encode proteins involved in axon repair and regeneration. The retrograde signal is transmitted through the fast retrograde transport pathway that moves key proteins to the nucleus.

Part of the repair process involves moving structural proteins from the region of the axon that is undamaged toward the site of damage. This movement uses slow anterograde transport which ultimate determines the rate of axon growth and repair (about 1 mm/day)

Schwann Cells and Axon Regrowth

Schwann cells generate the initial response to nerve injury. When a nerve is injured, Schwann cells near the site of injury undergo a dedifferentiation process and change from myelin producing cells to cells that lead the clean up of material in the damage nerve. In addition, the Schwann cells generate signals that recruit macrophages into the damaged nerve to help remove cell debris. Schwann cells also guide the direction of axon growth. They appear to produce molecules that interact with receptors at the leading edge of axon growth. The activation of the receptor stimulates growth of the axon in that direction. If the axon successfully regrows, the Schwann cells can remyelinate the axon. One consequence of axon regrowth and remyelination after injury is that the myelin layer is usually thinner than before injury.

Axons grow by extending a sheet-like projection of their cell membrane called a lamellipodia. From the lamellipodia, axons extend finger-like projections of the cell membrane called filopodia. These extensions follow the growth factors produced by cells in the extracellular matrix. In repair these cells are often the dedifferentiated Schwann cells. The growth factors can change the direction of axon growth by controlling the formation of lamellipodia and filopodia.

Axons grow through a combination of actin polymerization and microtubule polymerization. A network of actin filaments polymerizes to generate the force to push the leading edge of the axon cell membrane forward to form a lamellipodia. From the lamellipodia, small bundles of actin polymerize to form filopodia. Microtubules support this growth by delivering material important of actin polymerization. If a filopodia encounters a high concentration of a positive growth factor, it can orient the polymerization of actin and microtubules toward the filopodia so that the axon grows in that direction. Negative growth factors inhibit actin and microtubule polymerization so the axon stops growing in that direction.