An axo-axonic synapse is a type of

synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses fr ...

, formed by one

neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...

projecting its axon terminals onto another neuron’s

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action ...

. Axo-axonic synapses have been found and described more recently than the other more familiar types of synapses, such as axo-dendritic synapses and axo-somatic synapses. The spatio-temporal properties of neurons get altered by the type of synapse formed between neurons. Unlike the other types, the axo-axonic synapse does not contribute towards triggering an

action potential An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...

in the postsynaptic neuron. Instead, it affects the probability of

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...

release in the response to any action potential passing through the axon of the postsynaptic neuron. Thus, axo-axonic synapses appear to be very important for the

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

in achieving a specialized

neural computation Neural computation is the information processing performed by networks of neurons. Neural computation is affiliated with the philosophical tradition known as Computational theory of mind, also referred to as computationalism, which advances the th ...

. Axo-axonic synapses are found throughout the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

, including in the

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting o ...

and

striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...

in mammals; in the neuro-muscular junctions in

crustacean Crustaceans (Crustacea, ) form a large, diverse arthropod taxon which includes such animals as decapods, seed shrimp, branchiopods, fish lice, krill, remipedes, isopods, barnacles, copepods, amphipods and mantis shrimp. The crustacean gro ...

s; and in the visual circuitry in

dipterans Flies are insects of the order Diptera, the name being derived from the Greek δι- ''di-'' "two", and πτερόν ''pteron'' "wing". Insects of this order use only a single pair of wings to fly, the hindwings having evolved into advanced ...

. Axo-axonic synapses can induce either

inhibitory An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...

excitatory In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...

effects in the postsynaptic neuron. A classic example of the role of axo-axonic synapses is causing inhibitory effects on

motoneurons A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirec ...

in the spinal-somatic reflex arc. This phenomenon is known as presynaptic-inhibition.

Background

Complex interconnections of

s form

neural networks A neural network is a network or circuit of biological neurons, or, in a modern sense, an artificial neural network, composed of artificial neurons or nodes. Thus, a neural network is either a biological neural network, made up of biological ...

, which are responsible for various types of

computation Computation is any type of arithmetic or non-arithmetic calculation that follows a well-defined model (e.g., an algorithm). Mechanical or electronic devices (or, historically, people) that perform computations are known as '' computers''. An esp ...

in the brain. Neurons receive inputs mainly through

dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the ...

s, which play a role in spatio-temporal computation, leading to the firing of an

which subsequently travels to

synaptic terminals Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

passing through

s. Based on their locations,

s can be classified into various kinds, such as axo-dendritic synapse, axo-somatic synapse, and axo-axonal synapse. The prefix here indicates the part of the presynaptic neuron (i.e., ‘axo-’ for axons), and the suffix represents the location where the synapse is formed on the postsynaptic neuron (i.e., ‘-dendritic’ for dendrites, ‘-somatic’ for cell body and ‘-axonic’ for synapses on axons). Synapse location will govern the role of that synapse in a network of neurons. In axo-dendritic synapses, the presynaptic activity will affect the spatio-temporal computation in postsynaptic neurons by altering electrical potential in the dendritic branch. Whereas the axo-somatic synapse will affect the probability of firing an action potential in the postsynaptic neuron by causing

effects directly at the

cell body The soma (pl. ''somata'' or ''somas''), perikaryon (pl. ''perikarya''), neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. The word 'soma' comes from the Greek '' σῶ� ...

. Whereas the other types of synapses modulate postsynaptic neural activity, the axo-axonic synapses show subtle effects on the network-level neural information transfer. In such synapses, the activity in presynaptic neurons will ''not'' change the

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charge ...

(i.e., depolarize or hyperpolarize) of the cell body of postsynaptic neurons because presynaptic neurons project directly on the axons of the postsynaptic neurons. Thus, the axo-axonic synapse will mainly affect the probability of

vesicle release in response to an action potential firing in the postsynaptic neuron. Unlike other kinds of synapses, the axo-axonic synapse manipulates the effects of a postsynaptic neuron’s firing on the neurons further downstream in the network. Due to the mechanism of how axo-axonic synapses work, most of these synapses are inhibitory, and yet a few show excitatory effects in postsynaptic neurons.

History

The first direct evidence of the existence of axo-axonic synapses was provided by E. G. Gray in 1962. Gray produced electron microscopy photographs of axo-axonic synapses formed on the terminals of muscle afferents involved in the spinal somatic

reflex arc A reflex arc is a neural pathway that controls a reflex. In vertebrates, most sensory neurons do not pass directly into the brain, but synapse in the spinal cord. This allows for faster reflex actions to occur by activating spinal motor neuro ...

in a cat’s spinal cord slices. Later, Gray coined the term ‘axo-axonic’ after getting photographic confirmation from as many as twelve axo-axonic synapses. Within the next two years, scientists found axo-axonic synapses in various other places in the nervous system in different animals, such as in the

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

of cats and pigeons, in the

lateral geniculate nucleus In neuroanatomy, the lateral geniculate nucleus (LGN; also called the lateral geniculate body or lateral geniculate complex) is a structure in the thalamus and a key component of the mammalian visual pathway. It is a small, ovoid, ventral proj ...

of monkeys, in the

olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (O ...

of mice, and in various lobes in the octopus brain. This further confirmed the existence of axo-axonic synapses in the brain across animal phyla. Prior to the discovery of axo-axonic synapses,

physiologists Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical and ...

predicted the possibility of such mechanisms as early as in year 1935, following their observations of electrophysiological recordings and quantal analysis of brain segments. They had observed inhibitory responses in postsynaptic motoneurons in the slice preparation of the monosynaptic reflex arc. During simultaneous recordings from presynaptic and postsynaptic neurons, the physiologists could not make sense of the infrequent inhibition observed in the postsynaptic neuron, with no

changes in the presynaptic neuron. At that time, this phenomenon was known as “presynaptic inhibitory action”, the term proposed by Karl Frank in 1959 and later well summarized by John Eccles in his book. After Gray’s finding of the axo-axonic synapse in 1962, scientists confirmed that this phenomenon was in fact due to the axo-axonic synapse present in the reflex arc. More recently, in 2006 researchers discovered the first evidence of excitatory effects caused by an axo-axonic synapse. They found that GABAergic neurons project onto the axons of

pyramidal cell Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal co ...

s in the

to form axo-axonic synapse and elicit excitatory effects in cortical microcircuits.

Function

Below are the brain locations where axo-axonic synapses are found in different animals.

Cerebellar cortex

Axo-axonic synapse in cerebellum by Cajal

The axo-axonic synapse in the

cerebellar cortex The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebe ...

originally appeared in one of the drawings of

Santiago Ramón y Cajal Santiago Ramón y Cajal (; 1 May 1852 – 17 October 1934) was a Spanish neuroscientist, pathologist, and histologist specializing in neuroanatomy and the central nervous system. He and Camillo Golgi received the Nobel Prize in Physiology or Me ...

in his book published in 1909. Later using

electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a ...

, it was confirmed that the

basket cell Basket cells are inhibitory GABAergic interneurons of the brain, found throughout different regions of the cortex and cerebellum. Anatomy and physiology Basket cells are multipolar GABAergic interneurons that function to make inhibitory synapses ...

axon projects on the

axon hillock The axon hillock is a specialized part of the cell body (or soma) of a neuron that connects to the axon. It can be identified using light microscopy from its appearance and location in a neuron and from its sparse distribution of Nissl substance. ...

Purkinje cell Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Structure The ...

s in the cerebellar cortex in cats and other mammals, forming axo-axonic synapses. The first electrophysiological characterization of an axo-axonic synapse formed on Purkinje cells was done in 1963, where the presynaptic basket cell axons were found to inhibit the terminal output of postsynaptic Purkinje cells through the axo-axonic synapse. Network-level study revealed that the

granule cell A granule is a large particle or grain. It can refer to: * Granule (cell biology), any of several submicroscopic structures, some with explicable origins, others noted only as cell type-specific features of unknown function ** Azurophilic granul ...

s (''a.k.a.'' the parallel fibers) which activated Purkinje cells, also activated the basket cells which subsequently inhibited the effect of Purkinje cells on the downstream network.

Cerebral cortex

Axo-axonic synapses are found In the

visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...

(in V1 and V2) in mammals, and have been well studied in cats, rats and primates such as monkeys. The synapse is formed on the initial segments of the axons of pyramidal cells in several layers in the visual cortex. The projecting neurons for these synapses come from various parts of the

and

neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...

. Similarly, axo-axonic synapses are found in the

motor cortex The motor cortex is the region of the cerebral cortex believed to be involved in the planning, control, and execution of voluntary movements. The motor cortex is an area of the frontal lobe located in the posterior precentral gyrus immediately ...

, in the

subiculum The subiculum (Latin for "support") is the most inferior component of the hippocampal formation. It lies between the entorhinal cortex and the CA1 subfield of the hippocampus proper. The subicular complex comprises a set of related structures ...

and in the

piriform cortex The piriform cortex, or pyriform cortex, is a region in the brain, part of the rhinencephalon situated in the cerebrum. The function of the piriform cortex relates to the sense of smell. Structure The piriform cortex is part of the rhinencepha ...

. In the striate cortex, as the Golgi’s method and

revealed, as many as five axo-axonic synapses are formed onto a single pyramidal cell. In the

, inhibitory axo-axonic synapses may play a widespread role in network level activity by enabling synchronized firing of pyramidal cells, essentially by modulating the threshold for output of these cells. These synapses are also found on the initial segments of axons in pyramidal cells in the

somatosensory cortex In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch ( haptic perception), as well as temperature ( thermoception), body position ( proprioception), and pain. It ...

, and in the

primary olfactory cortex The primary olfactory cortex (POC) is a portion of the cerebral cortex. It is found in the inferior part of the temporal lobe of the brain. It receives input from the olfactory tract. It is involved in the sense of smell (olfaction). Structure ...

which are found to be the inhibitory kind. Studying the locations of axo-axonic synapses in the primary olfactory cortex, researchers have suggested that axo-axonic synapses may play a critical role in synchronizing

oscillations Oscillation is the repetitive or periodic variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples of oscillation include a swinging pendulum ...

in the piriform cortex (in the olfactory cortex), which aids olfaction. The axo-axonic synapses are also found in the

. These synapses are found to be formed mainly on principal cells in

stratum oriens Hippocampus anatomy describes the physical aspects and properties of the hippocampus, a neural structure in the medial temporal lobe of the brain. It has a distinctive, curved shape that has been likened to the sea-horse monster of Greek mythol ...

and stratum pyramidale and rarely on stratum radiatum; they commonly receive projections from

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...

local

interneuron Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. ...

s. The horizontal interneurons show a laminar distribution of dendrites and are involved in axo-axonic synapses in the hippocampus, which get direct synaptic inputs from CA1 pyramidal cells. Thus, in general, these studies indicate that axo-axonic synapses can provide a basic mechanism of information processing in the

Basal ganglia

Microscopy studies in the

previously suggested rare occurrence of axo-axonic synapses in individual sections. Extrapolations from the topological data suggest much higher counts of such synapses in the striatum where the therapeutic role of the axo-axonic synapses in treating

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...

has been postulated previously. In this study, authors examined 4,811 synapses in rat striatum sections, and 15 of them were found to be the axo-axonic synapses. These axo-axonic synapses are formed by

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate do ...

inhibitory interneurons (on the presynaptic side) projecting onto the axons of

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain. Examples include excitatory amino acid agonist, excitato ...

cortico-striatal fibers in the rat striatum.

Brainstem

Axo-axonic synapses are found in the

spinal trigeminal nucleus The spinal trigeminal nucleus is a nucleus in the medulla that receives information about deep/crude touch, pain, and temperature from the ipsilateral face. In addition to the trigeminal nerve (CN V), the facial (CN VII), glossopharyngeal (CN IX ...

in the

brainstem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is ...

. Electron microscopy studies on the kitten brainstem quantified synaptogenesis of axo-axonic synapses in the spinal trigeminal nucleus at different development ages of the brain. Authors identified the synapses by counting

vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like feature ...

released in the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

, which can be observed in the

micrograph A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnify, magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken ...

s. Axo-axonic contacts are shown to consistently increase throughout the development period, starting from the age of 3 hours to the age of 27 days in kittens. The highest rate of

synaptogenesis Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenes ...

is during the first 3 to 6 days, at the end of which, the kitten’s spinal trigeminal nucleus will have nearly half of the axo-axonic synapses present in adult cats. Later, between 16 to 27 days of age, there is another surge of axo-axonic synaptogenesis. Axo-axonic synapses are also observed in the

solitary nucleus In the human brainstem, the solitary nucleus, also called nucleus of the solitary tract, nucleus solitarius, and nucleus tractus solitarii, (SN or NTS) is a series of purely sensory nuclei (clusters of nerve cell bodies) forming a vertical column ...

(also known as nucleus of the solitary tract) uniquely in the commissural portion in the neuroanatomical studies, which used ''5-hydroxydopamine'' to label axo-axonic synapses. Axo-axonic synapses are formed on

baroreceptor Baroreceptors (or archaically, pressoreceptors) are sensors located in the carotid sinus (at the bifurcation of external and internal carotids) and in the aortic arch. They sense the blood pressure and relay the information to the brain, so that ...

terminals by the presynaptic

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

fibers, and are proposed to play a role in

baroreflex The baroreflex or baroreceptor reflex is one of the body's homeostasis, homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. The baroreflex provides a rapid negative feedback loop in which an elevated blood pressu ...

Spinal Cord

Axo-axonic synapses are found in the mammalian spinal reflex arc and in

Substantia gelatinosa of Rolando The apex of the posterior grey column, one of the three grey columns of the spinal cord, is capped by a V-shaped or crescentic mass of translucent, gelatinous neuroglia, termed the substantia gelatinosa of Rolando (or SGR) (or gelatinous substa ...

(SGR). In the spinal cord, axo-axonic synapses are formed on the terminals of sensory neurons with presynaptic inhibitory interneurons. These synapses are first studied using intracellular recordings from the spinal motoneurons in cats, and have been shown to cause presynaptic inhibition. This seems to be a common mechanism in spinal cords, in which

interneurons inhibit presynaptic activity in sensory neurons and eventually control activity in motor neurons enabling selective control of muscles. In efforts to quantify the occurrence of axo-axonic synapses in the SGR region in rats, 54 such synapses were found among the total 6,045 synapses examined. These 54 axo-axonic synapses were shown to have either agranular vesicles or large granular vesicles.

Vestibular system

Axo-axonic synapses are found in the

lateral vestibular nucleus The lateral vestibular nucleus (Deiters's nucleus) is the continuation upward and lateralward of the principal nucleus, and in it terminate many of the ascending branches of the vestibular nerve. Structure It consists of very large multipolar cel ...

in rats. Axo-axonic synapses are formed from the small axons of interneurons onto the axon terminals of large axons, which are upstream to the main dendritic stem. Interestingly, the authors claimed that axo-axonic synapses, which are abundant in rats, are absent in the lateral vestibular nucleus in cats. They note that the types of axon terminals identified and described in cats are all found in rats, but the reverse is not true because the axons forming the axo-axonic synapses are missing in cats. These synapses are proposed to enable complex

for the vestibular reflex in rats.

Hindbrain

Axo-axonic synapses are found in the

mauthner cell The Mauthner cells are a pair of big and easily identifiable neurons (one for each half of the body) located in the rhombomere 4 of the hindbrain in fish and amphibians that are responsible for a very fast escape reflex (in the majority of animal ...

s in goldfish. The

and initial axon segments of mauthner cells receive terminals from extremely fine

unmyelinated Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

fibers, which cover the axon hillock with helical projections. These helical projections around mauthner cells are also known as the axon cap. The difference between the axo-axonic synapses and other synapses on mauthner cells is that synapses on dendrites and soma receive myelinated fibers, while axons receive unmyelinated fibers. Mauthner cells are big neurons which are involved in fast

escape reflex Escape reflex, or escape behavior, is any kind of escape response found in an animal when it is presented with an unwanted stimulus. It is a simple reflectory reaction in response to stimuli indicative of danger, that initiates an escape motion ...

es in fish. Thus, these axo-axonic synapses could selectively disable the escape network by controlling the effect of mauthner cells on the neural network further downstream. Studying the morphological variation of the axo-axonic synapses at the axon hillock in mauthner cells suggests that, evolutionarily, these synapses are more recent than the mauthner cells. Response to the startle can be mapped

phylogenetically In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...

, which confirms that basal actinopterygian fish, with little to no axo-axonic synapses on mauthner cells, show worse escape response than fish with axo-axonic synapses.

Neuromuscular junction

Inhibitory axo-axonic synapses are found in the

neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation ...

s and have been widely studied in Crayfish. Axo-axonic synapses are formed on the excitatory axons as a postsynaptic neuron by the motor neurons from the presynaptic side. Motor neurons, which is the common inhibitor in crab limb closers and limb accessory flexors, form axo-axonic synapses in addition to the

with the muscles in crayfish. These synapses were first observed in 1967, when they were found to cause presynaptic inhibition in leg muscles of crayfish and crabs. Subsequent studies found that axo-axonic synapses showed varying numbers of occurrence based on the location of the leg muscles from the nervous system. For instance, proximal regions have thrice as many axo-axonic synapses than the central regions. These synapses are proposed to function by limiting

neurotransmitter release Exocytosis () is a form of active transport and bulk transport in which a cell transports molecules (e.g., neurotransmitters and proteins) out of the cell ('' exo-'' + ''cytosis''). As an active transport mechanism, exocytosis requires the use of ...

for controlled leg movements.

Clinical Significance

An example of the physiological role of axo-axonic synapses, which are formed by

inhibitory

s to the axons of

s, is in eliciting spontaneous seizures, which is a key symptom of Intractable

Epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

. The presynaptic inhibitory interneurons, which can be labeled by

cholecystokinin Cholecystokinin (CCK or CCK-PZ; from Greek ''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (gallbladder)'') is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat an ...

and

GAT-1 GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the ''SLC6A1'' gene and belongs to the solute carrier 6 (SLC6) family of transporters. It mediates gamma-aminobutyr ...

, are found to modulate the granule cells’s spike output. The same cells subsequently project excitatory mossy fibers to

pyramidal neurons Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal co ...

in the hippocampal

CA3 region The hippocampus proper refers to the actual structure of the hippocampus which is made up of three regions or subfields. The subfields CA1, CA2, and CA3 use the initials of cornu Ammonis, an earlier name of the hippocampus. Structure There are ...

. One of the two leading theories for the pathoetiology of

is the glutamate theory.

Glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

is a well studied neurotransmitter for its role in learning and memory, and also in the brain development during

prenatal Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...

and childhood. Studies of rat striatum found inhibitory axo-axonic synapses formed on the glutamatergic cortico-striatal fibers. They proposed that these axo-axonic synapses in the striatum could be responsible for inhibiting the glutamatergic neurons. Additionally, these dopaminergic synapses are also proposed to cause hyperdopaminergic activity and become

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

for the postsynaptic glutamatergic neurons. This mechanism is proposed to be a possible mechanism for glutamate dysfunction in observed schizophrenia.

Development

A study on the

spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...

in mice suggests that the sensory Ig/ Caspr4 complex is involved in the formation of axo-axonic synapses on

proprioceptive Proprioception ( ), also referred to as kinaesthesia (or kinesthesia), is the sense of self-movement, force, and body position. It is sometimes described as the "sixth sense". Proprioception is mediated by proprioceptors, mechanosensory neuron ...

afferents. These synapses are formed through projection of

interneurons on

sensory neuron Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The ...

s, which is upstream to the motor neurons. In the axo-axonic synapse, expressing NB2 (Contactin5)/Caspr4 coreceptor complex in postsynaptic neurons along with expressing NrCAM/CHL1 in presynaptic interneurons results in the increased numbers of such synapses forming in the spinal cord. Also, knocking out NB2 from the sensory neurons reduced the number of axo-axonic synapses from GABAergic interneurons, which suggests the

necessity Necessary or necessity may refer to: * Need ** An action somebody may feel they must do ** An important task or essential thing to do at a particular time or by a particular moment * Necessary and sufficient condition, in logic, something that is ...

and the role of NB2 in

of axo-axonic type of synapses.

Background

History

Function

Cerebellar cortex

Cerebral cortex

Basal ganglia

Brainstem

Spinal Cord

Vestibular system

Hindbrain

Neuromuscular junction

Clinical Significance

Development

See also

References

Further reading