The nervous system has three levels of organization:

An axon often has to navigate great distance to reach its target cell (ie, another neuron or muscle fiber) and establish the synaptic connection. This process is axonal pathfinding. The axon does not navigate its natural pathway due to any single cue, but via combinations of signals. This redundancy makes axonal pathfinding extremely complex. Axonal pathfinding is extremely specific: a particular axon always contacts the same (or at least very similar) set of neurons or muscles.

Neurons have an intrinsic polarity that is always the same for a specific type of neuron. At one end of this polarity, a localized increase in cell membrane activity occurs (with ruffles, aka lamellipodium often visible) and fine filopodia of the cell cytoplasm extend and withdraw. The structure of filopodia is maintained by microfilaments, while axonal strucure is maintained by microtubules. Eventually, a filopodium forms a growth cone, an actively motile region at the far end.

The growth cone travels based on cues from a substrate called the extracellular matrix (ECM). The ECM contains laminin, collagen and fibronectin (the first being the most important) that adhere to cadherins and integrins in the growth cone membrane. Also, the ECM contains unique molecules (ie, nerve growth factor and retinoic acid) that guide the growth cone, sometimes across a gradient and other times along a narrow path. These unique molecules are deposited: by tissues over which the axons grow (ie, epithelia, somites and blood vessels); by cells at crucial migratory points; and even by the target tissue itself.

Once the growth cone reaches its specific target (ie, muscle fibers or another neuron) it must stop growing and establish a synaptic connection. The high specificity of axonal pathfinding is determined by any of three ways:

Netrin

Commisural neurons are interneurons in the (usually dorsal) spinal cord that extend their axons across the midline. Commisural projects project ventrally toward the floor plate, and then cross the midline ventral to the floorplate of the spinal cord. Recombination experiments have shown that the floor plate secretes netrin, an attractive signal critical for commisural axons to migrate to the floor plate and cross the midline. In netrin^-/- mutants, commisural axons fail to grow to the floor plate.

Ehprin

Ephrins are membrane-bound ligands that bind to membrane-bound ephrin-receptors called ephs. When an ephrin and an eph bind, a signal is generated in both cells — this means the signal is bi-directional. Ephins are repulsive signals in axon migration, with ephrin/eph signaling responsible for setting the retino-tectal topographic map. In a topographic map, the spatial organization of neurons in one region (retina) is replicated in a connected region (tectum). The retina and tectum contain inverse gradients of ephs and ephrins; axons extend from the retina to the tectum until reaching a signaling threshold (inversely proportionate to their starting point) that inhibits further navigation. Thus, axons from a retinal region with low levels eph will target a tectal region with high levels of eph. In the figure below, axons from a given retinal quadrant will target the tectal quadrant of matching color.

All in all, ephrin/eph signaling is critical for:

1. motor neurons extending only through the anterior of a somite;
2. setting the retino-tectal topographic map;
3. inhibiting mixing — rhombomeres, compartments in the hindbrain across which cells do not mix, express ephrins and ephs.

Neurons cluster together to form ganglia. Usually, one ganglia is larger and more central than others. This ganglia is called the brain. In vertebrates, most cells of the nervous system are found in the brain and spinal cord. This is where most information processing, storage and retrieval occurs.

Neurons vary considerably in size and shape, but have 3 principal components: a cell body and two types of cytoplasmic extensions (an axon and dendrites).

All but one type of neuroglia (glial cells) are derived from same ectoderm that produces neurons. Most organs are from the mesoderm. There are six categories of neuroglia:

• Neurolemmocytes (Schwann cells) form myelin layers around axons in the PNS.
• Oligodendrocytes form myelin layers around axons in the CNS.
• Microglia are derived from mesoderm and remove foreign and degenerated material in the CNS.
• Astrocytes help regulate passage of molecules from blood to brain.
• Ependymal cells line brain ventricles and central canal of spinal cord
• Ganglionic gliocytes support neuron cell bodies within ganglia off the PNS.

The Sodium/Potassium Pump puts Na⁺ outside the cell and K⁺ inside the cell.

• 3Na⁺ mols inside bind to receptor
• This stimualtes phosphorylation of receptor by ATP.
• This alters receptor shape, shape change dumps Na⁺ onto inside.
• Open receptors bind 2K⁺ ions outside.
• K⁺ binding triggers phosphate release.
• This restores original conformation.
• K⁺ released inside, NA⁺ sites become available.
• Net: 1 ATP lost; 3 Na⁺ outside; 2 K⁺ inside.

Voltage is the tendency for electrically charged particles such as electrons or ions to move between two points. The principle of voltage is the foundation for action potentials. The action potential is a wave of depolarization of a neuron’s plasma membrane. This depolarization requires a resting membrane potential of about -70 millivolts, with the interior of the cell negatively charged. Two proteins are required to establish the resting membrane potential:

Na⁺ ATPase and potassium leak channels are the two proteins required to establish the resting membrane potential. These proteins are integral membrane proteins in the plasma membrane. The Na⁺K⁺ ATPase hydrolizes one ATP molecule to pumps three sodium ions out of the cell and two potassium ions into the cell. The Na⁺K⁺ ATPase uses ATP to drive transport against their gradient. This transport of ions against their gradient, while hydrolizing ATP, is an example of primary active transport. The result is a gradient with plentiful sodium outside the cell and plentiful potassium inside the cell.

Potassium leak channels allow potassium ions, but no other ions, to flow down their gradient. Since Na⁺K⁺ ATPase causes an overabundance of potassium ions inside the cell, the potassium ions will flow through the potassium leak channels back outside the cell. Since potassium ions are positive, they will leave the interior of the cell with a net negative charge. The potential across the plasma membrane is about -70mV, the resting membrane potential.

All cells have a resting membrane potential; neurons and muscle tissues are unique in using the resting membrane potential to generate action potentials. The flow of potassium out of the cell makes the interior of the cell more negatively charged. If the potassium leak channels were blocked, the interior of the cell would have a less negative (more positive) charge. If sodium ions were allowed to flow down their concentration gradient, they would flow into the cell and the interior of the cell would have a less negative (more positive) charge.

The resting membrane potential establishes a negative charge along the interior of the axons along with the rest of the neuronal interior. An action potential is a disturbance in this membrane potential, a localized depolarization of the plasma membrane that travels in a wave-like manner along an axon. Depolarization is a change in the membrane potential from the resting membrane potential of approximately -70 mV to a less negative or even positive potential. The change in membrane potential during an action potential is caused by movement of ions into and out of the neuron through ion channels. The action potential is not strictly an electrical impulse, like electrons moving in a copper telephone wire, but an electrochemical impulse.

A key protein in the propagation of action potentials are the voltage-gated soidum channels located in the plasma membrane of the axon. In response to a change in the membrane potential, these ion channels open to allow sodium ions to flow down a gradient into the cell and depolarize that section of membrane. Opening the voltage-gated sodium channels would allow sodium ions to flow into the cell (down the concentration gradient) and make the interior of the cell less negatively, or even positively, charged. These channels are opened by depolarization of the membrane from the resting potential of -70 mV to a threshold potential of approximately -50 mV. Once this threshold is reached, the channels are opened fully; below this threshold, though, they do not allow the pssage of any ions through the channel. When channels open, sodium flows into the cell (down the concentration gradient) and depolarizes that section of the membrane to about +35 mV before inativating. Some of the sodium ions flow down the interior of the axon, slightly depolarizing the neighboring sectino of the membrane. Whn the depolarization reaches -50 mV i the next section of membrane, those voltage-gated sodium channels open as well. This opening of more voltage-gated sodium channels passes the depolarization down the axon. Since action potentials are continually renewed at each point in the axon as they travel, action potentials can’t run out of energy before reaching a synapse. Once they begin, they will not stop until that synapse is reahed.

After depolarization, repolarization returns the membrane potential to normal.

na+ channels open to gwenerate an action potential
upstream na+ channels inactivate making membrane refractory…K_ channels open and axon repolarizes
action potential jumps quickly to new node and contnues from node to node

Steps in an Action Potential:

1. At rest the outside of the membrane is more positive than the inside.
2. Sodium moves inside the cell causing an action potential.
3. The positive sodium ion influx makes the inside of the membrane more positive than the outside
4. Potassium ions flow out of the cell, restoring the resting potential net charges.
5. Sodium ions are pumped out of the cell and potassium ions are pumped into the cell, restoring the original distribution of ions.