potential is that it is "all-or-nothing" – every action potential that an axon generates has essentially the same size and shape. this all-or-nothing characteristic allows action potentials to be transmitted from one end of a long axon to the other without any reduction in size. there are, however, some types of neurons with short axons that carry graded electrochemical signals, of variable amplitude. when an action potential reaches a presynaptic terminal, it activates the synaptic transmission process. the first step is rapid opening of calcium ion channels in the membrane of the axon, allowing calcium ions to flow inward across the membrane. the resulting increase in intracellular calcium concentration causes synaptic vesicles (tiny containers enclosed by a lipid membrane) filled with a neurotransmitter chemical to fuse with the axon's membrane and empty their contents into the extracellular space. the neurotransmitter is released from the presynaptic nerve through exocytosis. the neurotransmitter chemical then diffuses across to receptors located on the membrane of the target cell. the neurotransmitter binds to these receptors and activates them. depending on the type of receptors that are activated, the effect on the target cell can be to excite the target cell, inhibit it, or alter its metabolism in some way. this entire sequence of events often takes place in less than a thousandth of a second. afterward, inside the presynaptic terminal, a new set of vesicles is moved into position next to the membrane, ready to be released when the next action potential arrives. the action potential is the final electrical step in the integration of synaptic messages at the scale of the neuron. (a) pyramidal cell, interneuron, and short durationwaveform (axon), overlay of the three average waveforms;(b) average and standard error of peak-trough time for pyramidal cells interneurons, and putative axons;(c) scatter plot of signal to noise ratios for individual units againstpeak-trough time for axons, pyramidal cells (pyr) and interneurons (int). extracellular recordings of action potential propagation in axons has been demonstrated in freely moving animals. while extracellular somatic action potentials have been used to study cellular activity in freely moving animals such as place cells, axonal activity in both white and gray matter can also be recorded. extracellular recordings of axon action potential propagation is distinct from somatic action potentials in three ways: 1. the signal has a shorter peak-trough duration (~150μs) than of pyramidal cells (~500μs) or interneurons (~250μs). 2. the voltage change is triphasic. 3. activity recorded on a tetrode is seen on only one of the four recording wires. in recordings from freely moving rats, axonal signals have been isolated in white matter tracts including the alveus and the corpus callosum as well hippocampal gray matter. in fact, the generation of action potentials in vivo is sequential in nature, and these sequential spikes constitute the digital codes in the neurons. although previous studies indicate an axonal origin of a single spike evoked by short-term pulses, physiological signals in vivo trigger the initiation of sequential spikes at the cell bodies of the neurons. in addition to propagating action potentials to axonal terminals, the axon is able to amplify the action potentials, which makes sure a secure propagation of sequential action potentials toward the axonal terminal. in terms of molecular mechanisms, voltage-gated sodium channels in the axons possess lower threshold and shorter refractory period in response to short-term pulses. development and growth development the development of the axon to its target, is one of the six major stages in the overall development of the nervous system. studies done on cultured hippocampal neurons suggest that neurons initially produce multiple neurites that are equivalent, yet only one of these neurites is destined to become the axon. it is unclear whether axon specification precedes axon elongation or vice versa, although recent evidence points to the latter. if an axon that is not fully developed is cut, the polarity can change and other neurites can potentially become the axon. this alteration of polarity only occurs when the axon is cut at least 10 μm shorter than the other neurites. after the incision is made, the longest neurite will become the future axon and all the other neurites, including the original axon, will turn into dendrites. imposing an external force on a neurite, causing it to elongate, will make it become an axon. nonetheless, axonal development is achieved through a complex interplay between extracellular signaling, intracellular signaling and cytoskeletal dynamics. extracellular signaling the extracellular signals that propagate through the extracellular matrix surrounding neurons play a prominent role in axonal development. these signaling molecules include proteins, neurotrophic factors, and extracellular matrix and adhesion molecules. netrin (also known as unc-6) a secreted protein, functions in axon formation. when the unc-5 netrin receptor is mutated, several neurites are irregularly projected out of neurons and finally a single axon is extended anteriorly. the neurotrophic factors – nerve growth factor (ngf), brain-derived neurotrophic factor (bdnf) and neurotrophin-3 (ntf3) are also involved in axon development and bind to trk receptors. the ganglioside-converting enzyme plasma membrane ganglioside sialidase (pmgs), which is involved in the activation of trka at the tip of neutrites, is required for the elongation of axons. pmgs asymmetrically distributes to the tip of the neurite that is destined to become the future axon. intracellular signaling during axonal development, the activity of pi3k is increased at the tip of destined axon. disrupting the activity of pi3k inhibits axonal development. activation of pi3k results in the production of phosphatidylinositol (3,4,5)-trisphosphate (ptdins) which can cause significant elongation of a neurite, converting it into an axon. as such, the overexpression of phosphatases that dephosphorylate ptdins leads into the failure of polarization. cytoskeletal dynamics the neurite with the lowest actin filament content will become the axon. pgms concentration and f-actin content are inversely correlated; when pgms becomes enriched at the tip of a neurite, its f-actin content is substantially decreased. in addition, exposure to actin-depolimerizing drugs and toxin b (which inactivates rho-signaling) causes the formation of multiple axons. consequently, the interruption of the actin network in a growth cone will promote its neurite to become the axon. growth axon of nine-day-old mouse with growth cone visible growing axons move through their environment via the growth cone, which is at the tip of the axon. the growth cone has a broad sheet-like extension called a lamellipodium which contain protrusions called filopodia. the filopodia are the mechanism by which the entire process adheres to surfaces and explores the surrounding environment. actin plays a major role in the mobility of this system. environments with high levels of cell adhesion molecules (cams) create an ideal environment for axonal growth. this seems to provide a "sticky" surface for axons to grow along. examples of cams specific to neural systems include n-cam, tag-1 – an axonal glycoprotein – and mag, all of which are part of the immunoglobulin superfamily. another set of molecules called extracellular matrix-adhesion molecules also provide a sticky substrate for axons to grow along. examples of these molecules include laminin, fibronectin, tenascin, and perlecan. some of these are surface bound to cells and thus act as short range attractants or repellents. others are difusible ligands and thus can have long range effects. cells called guidepost cells assist in the guidance of neuronal axon growth. these cells that help axon guidance, are typically other neurons that are sometimes immature. when the axon has completed its growth at its connection to the target, the diameter of the axon can increase by up to five times, depending on the speed of conduction required. it has also been discovered through research that if the axons of a neuron were damaged, as long as the soma (the cell body of a neuron) is not damaged, the axons would regenerate and remake the synaptic connections with neurons with the help of guidepost cells. this is also referred to as neuroregeneration. nogo-a is a type of neurite outgrowth inhibitory component that is present in the central nervous system myelin membranes (found in an axon). it has a crucial role in restricting axonal regeneration in adult mammalian central nervous system. in recent studies, if nogo-a is blocked and neutralized, it is possible to induce long-distance axonal regeneration which leads to enhancement of functional recovery in rats and mouse spinal cord. this has yet to be done on humans. a recent study has also found that macrophages activated through a specific inflammatory pathway activated by the dectin-1 receptor are capable of promoting axon recovery, also however causing neurotoxicity in the neuron. length regulation axons vary largely in length from a few micrometers up to meters in some animals. this emphasizes that there must be a cellular length regulation mechanism allowing the neurons both to sense the length of their axons and to control their growth accordingly. it was discovered that motor proteins play an important role in regulating the length of axons. based on this observation, researchers developed an explicit model for axonal growth describing how motor proteins could affect the axon length on the molecular level. these studies suggest that motor proteins carry signaling molecules from the soma to the growth cone and vice versa whose concentration oscillates in time with a length-dependent frequency. classification further information: nerve conduction velocity the axons of neurons in the human peripheral nervous system can be classified based on their physical features and signal conduction properties. axons were known to have different thicknesses (from 0.1 to 20 µm) and these differences were thought to relate to the speed at which an action potential could travel along the axon – its conductance velocity. erlanger and gasser proved this hypothesis, and identified several types of nerve fiber, establishing a relationship between the diameter of an axon and its nerve conduction velocity. they published their findings in 1941 giving the first classification of axons. axons are classified in two systems. the first one introduced by erlanger and gasser, grouped the fibers into three main groups using the letters a, b, and c. these groups, group a, group b, and group c include both the sensory fibers (afferents) and the motor fibers (efferents). the first group a, was subdivided into alpha, beta, gamma, and delta fibers – aα, aβ, aγ, and aδ. the motor neurons of the different motor fibers, were the lower motor neurons – alpha motor neuron, beta motor neuron, and gamma motor neuron having the aα, aβ, and aγ nerve fibers, respectively. later findings by other researchers identified two groups of aa fibers that were sensory fibers. these were then introduced into a system that only included sensory fibers (though some of these were mixed nerves and were also motor fibers). this system refers to the sensory groups as types and uses roman numerals: type ia, type ib, type ii, type iii, and type iv. motor lower motor neurons have two kind of fibers: motor fiber types typeerlanger-gasserclassificationdiameter(µm)myelinconduction velocity(meters/second)associated muscle fibers alpha (α) motor neuron aα13–20yes80–120extrafusal muscle fibers beta (β) motor neuron aβ gamma (γ) motor neuron aγ5-8yes4–24intrafusal muscle fibers sensory different sensory receptors innervate different types of nerve fibers. proprioceptors are innervated by type ia, ib and ii sensory fibers, mechanoreceptors by type ii and iii sensory fibers and nociceptors and thermoreceptors by type iii and iv sensory fibers. sensory fiber types typeerlanger-gasserclassificationdiameter(µm)myelinconductionvelocity (m/s)associated sensory receptorsproprioceptorsmechanoceptorsnociceptors andthermoreceptors ia aα13–20yes80–120primary receptors of muscle spindle (annulospiral ending)✔ ib aα13–20yes80–120golgi tendon organ ii aβ6–12yes33–75secondary receptors of muscle spindle (flower-spray ending).all cutaneous mechanoreceptors✔ iii aδ1–5thin3–30free nerve endings of touch and pressurenociceptors of lateral spinothalamic tractcold thermoreceptors✔ iv c0.2–1.5no0.5–2.0nociceptors of anterior spinothalamic tractwarmth receptors autonomic the autonomic nervous system has two kinds of peripheral fibers: fiber types typeerlanger-gasserclassificationdiameter(µm)myelinconductionvelocity (m/s) preganglionic fibers b1–5yes3–15 postganglionic fibers c0.2–1.5no0.5–2.0 clinical significance main articles: nerve injury, peripheral neuropathy, and demyelinating disease in order of degree of severity, injury to a nerve can be described as neurapraxia, axonotmesis, or neurotmesis. concussion is considered a mild form of diffuse axonal injury. axonal injury can also cause central chromatolysis. the dysfunction of axons in the nervous system is one of the major causes of many inherited neurological disorders that affect both peripheral and central neurons. when an axon is crushed, an active process of axonal degeneration takes place at the part of the axon furthest from the cell body. this degeneration takes place quickly following the injury, with the part of the axon