axo-axonic synapse

File:Axo-axonic synapse.svg

Complex interconnections of neurons form neural networks, which are responsible for various types of computation in the brain. Neurons receive inputs mainly through dendrites, which play a role in spatio-temporal computation, leading to the firing of an action potential which subsequently travels to synaptic terminals passing through axons.{{Cite book| vauthors = Saladin KS |title=Human anatomy|date=2011|publisher=McGraw-Hill|isbn=978-0-07-352560-0|edition=3rd|location=New York|oclc=318191613}} Based on their locations, synapses 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).{{Cite book|title=Principles of neural science|date=2000|publisher=McGraw-Hill, Health Professions Division|others=Kandel, Eric R., Schwartz, James H. (James Harris), 1932-2006., Jessell, Thomas M.|isbn=0-8385-7701-6|edition=4th|location=New York|oclc=42073108}} 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 inhibitory or excitatory effects directly at the cell body.{{Cite journal|last=Frank|first=Karl | name-list-style = vanc |date= June 1959 |title=Basic Mechanisms of Synaptic Transmission in the Central Nervous System|journal=IRE Transactions on Medical Electronics |volume=ME-6 |issue=2 |pages=85–88 |doi=10.1109/IRET-ME.1959.5007923 }}

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 (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 neurotransmitter 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.

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 in a cat's spinal cord slices.{{cite journal | vauthors = Gray EG | title = A morphological basis for pre-synaptic inhibition? | journal = Nature | volume = 193 | issue = 4810 | pages = 82–3 | date = January 1962 | pmid = 13901298 | doi = 10.1038/193082a0 | bibcode = 1962Natur.193...82G | s2cid = 4282950 | url = https://www.nature.com/articles/193082a0 | url-access = subscription }} 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 of cats and pigeons,{{cite journal | vauthors = Kidd M | title = Electron microscopy of the inner plexiform layer of the retina in the cat and the pigeon | journal = Journal of Anatomy | volume = 96 | pages = 179–87 | date = April 1962 | issue = Pt 2 | pmid = 14455782 | pmc = 1244141 }} in the lateral geniculate nucleus of monkeys,{{cite journal | vauthors = Colonnier M, Guillery RW | title = Synaptic organization in the lateral geniculate nucleus of the monkey | journal = Zeitschrift für Zellforschung und Mikroskopische Anatomie | volume = 62 | issue = 3 | pages = 333–55 | date = April 1964 | pmid = 14218147 | doi = 10.1007/BF00339284 | s2cid = 3173201 }} in the olfactory bulb of mice,{{cite journal | vauthors = Hirata Y | title = Some Observations on the Fine Structure of the Synapses in the Olfactory Bulb of the Mouse, with Particular Reference to the Atypical Synaptic Configurations | journal = Archivum Histologicum Japonicum = Nihon Soshikigaku Kiroku | volume = 24 | issue = 3 | pages = 293–302 | date = February 1964 | pmid = 14133696 | doi = 10.1679/aohc1950.24.293 | doi-access = free }} and in various lobes in the octopus brain.{{cite journal | vauthors = Gray EG, Young JZ | title = Electron Microscopy of Synaptic Structure of Octopus Brain | journal = The Journal of Cell Biology | volume = 21 | issue = 1 | pages = 87–103 | date = April 1964 | pmid = 14154498 | pmc = 2106419 | doi = 10.1083/jcb.21.1.87 }} This further confirmed the existence of axo-axonic synapses in the brain across animal phyla.

Prior to the discovery of axo-axonic synapses, physiologists predicted the possibility of such mechanisms as early as in year 1935, following their observations of electrophysiological recordings and quantal analysis of brain segments.{{cite journal | vauthors = Barron DH, Matthews BH | title = Intermittent conduction in the spinal cord | journal = The Journal of Physiology | volume = 85 | issue = 1 | pages = 73–103 | date = August 1935 | pmid = 16994699 | pmc = 1394492 | doi = 10.1113/jphysiol.1935.sp003303 }} 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 membrane potential 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 cells in the cerebral cortex to form axo-axonic synapse and elicit excitatory effects in cortical microcircuits.

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

File:Axo-axonic synapse in cerebellum by Cajal.jpg

The axo-axonic synapse in the cerebellar cortex originally appeared in one of the drawings of Santiago Ramón y Cajal in his book published in 1909.{{Cite book|last=Ramón y Cajal|first=Santiago | name-list-style = vanc |title=Histologie du système nerveux de l'homme & des vertébrés.|date=1909|publisher=Maloine|location=Paris|doi=10.5962/bhl.title.48637|url=https://www.biodiversitylibrary.org/bibliography/48637 }} Later using electron microscopy, it was confirmed that the basket cell axon projects on the axon hillock of Purkinje cells 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.{{cite journal | vauthors = Andersen P, Eccles J, Voorhoeve PE | title = Inhibitory Synapses on Somas of Purkinje Cells in the Cerebellum | journal = Nature | volume = 199 | issue = 4894 | pages = 655–6 | date = August 1963 | pmid = 14074549 | doi = 10.1038/199655a0 | bibcode = 1963Natur.199..655A | s2cid = 39375166 | url = https://www.nature.com/articles/199655a0 | url-access = subscription }} Network-level study revealed that the granule cells (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.{{cite journal | vauthors = Dizon MJ, Khodakhah K | title = The role of interneurons in shaping Purkinje cell responses in the cerebellar cortex | journal = The Journal of Neuroscience | volume = 31 | issue = 29 | pages = 10463–73 | date = July 2011 | pmid = 21775592 | pmc = 3314287 | doi = 10.1523/JNEUROSCI.1350-11.2011 }}

Axo-axonic synapses are found In the visual cortex (in V1 and V2) in mammals, and have been well studied in cats, rats and primates such as monkeys.{{cite journal | vauthors = Fairén A, Valverde F | title = A specialized type of neuron in the visual cortex of cat: a Golgi and electron microscope study of chandelier cells | journal = The Journal of Comparative Neurology | volume = 194 | issue = 4 | pages = 761–79 | date = December 1980 | pmid = 7204642 | doi = 10.1002/cne.901940405 | s2cid = 34356324 }}{{cite journal | vauthors = Lund JS, Boothe RG, Lund RD | title = Development of neurons in the visual cortex (area 17) of the monkey (Macaca nemestrina): a Golgi study from fetal day 127 to postnatal maturity | journal = The Journal of Comparative Neurology | volume = 176 | issue = 2 | pages = 149–88 | date = November 1977 | pmid = 410850 | doi = 10.1002/cne.901760203 | s2cid = 750242 }}{{cite journal | vauthors = Peters A, Proskauer CC, Ribak CE | title = Chandelier cells in rat visual cortex | journal = The Journal of Comparative Neurology | volume = 206 | issue = 4 | pages = 397–416 | date = April 1982 | pmid = 7096634 | doi = 10.1002/cne.902060408 | s2cid = 42805817 }}{{cite journal | vauthors = Somogyi P | title = A specific 'axo-axonal' interneuron in the visual cortex of the rat | journal = Brain Research | volume = 136 | issue = 2 | pages = 345–50 | date = November 1977 | pmid = 922488 | doi = 10.1016/0006-8993(77)90808-3 | s2cid = 7263036 }} 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 central nervous system and neocortex. Similarly, axo-axonic synapses are found in the motor cortex, in the subiculum and in the piriform cortex. In the striate cortex, as the Golgi's method and electron microscopy revealed, as many as five axo-axonic synapses are formed onto a single pyramidal cell. In the cerebral cortex, 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, and in the primary olfactory cortex which are found to be the inhibitory kind.{{cite journal | vauthors = Jones EG, Powell TP | title = Synapses on the axon hillocks and initial segments of pyramidal cell axons in the cerebral cortex | journal = Journal of Cell Science | volume = 5 | issue = 2 | pages = 495–507 | date = September 1969 | doi = 10.1242/jcs.5.2.495 | pmid = 5362338 }}{{cite journal | vauthors = Westrum LE | title = Electron microscopy of synaptic structures in olfactory cortex of early postnatal rats | journal = Journal of Neurocytology | volume = 4 | issue = 6 | pages = 713–32 | date = December 1975 | pmid = 1194932 | doi = 10.1007/BF01181632 | s2cid = 8710902 }} 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 in the piriform cortex (in the olfactory cortex), which aids olfaction.{{cite journal | vauthors = Wang X, Sun QQ | title = Characterization of axo-axonic synapses in the piriform cortex of Mus musculus | journal = The Journal of Comparative Neurology | volume = 520 | issue = 4 | pages = 832–47 | date = March 2012 | pmid = 22020781 | pmc = 3903392 | doi = 10.1002/cne.22792 }} The axo-axonic synapses are also found in the hippocampus. These synapses are found to be formed mainly on principal cells in stratum oriens and stratum pyramidale and rarely on stratum radiatum; they commonly receive projections from GABAergic local interneurons.{{cite journal | vauthors = Ganter P, Szücs P, Paulsen O, Somogyi P | title = Properties of horizontal axo-axonic cells in stratum oriens of the hippocampal CA1 area of rats in vitro | journal = Hippocampus | volume = 14 | issue = 2 | pages = 232–43 | date = 2004 | pmid = 15098728 | doi = 10.1002/hipo.10170 | s2cid = 2993178 }} 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 cerebral cortex.{{cite journal | vauthors = Peters A, Proskauer CC, Kaiserman-Abramof IR | title = The small pyramidal neuron of the rat cerebral cortex. The axon hillock and initial segment | journal = The Journal of Cell Biology | volume = 39 | issue = 3 | pages = 604–19 | date = December 1968 | pmid = 5699934 | pmc = 2107556 | doi = 10.1083/jcb.39.3.604 }}

Microscopy studies in the striatum 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 has been postulated previously.{{cite journal | vauthors = Kornhuber J, Kornhuber ME | title = Axo-axonic synapses in the rat striatum | language = en | journal = European Neurology | volume = 22 | issue = 6 | pages = 433–6 | date = 1983 | pmid = 6662154 | doi = 10.1159/000115598 | url = https://www.karger.com/Article/FullText/115598 | url-access = subscription }} 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 inhibitory interneurons (on the presynaptic side) projecting onto the axons of glutamatergic cortico-striatal fibers in the rat striatum.

Axo-axonic synapses are found in the spinal trigeminal nucleus in the brainstem.{{cite journal | vauthors = Dunn RC, Westrum LE, Dikmen SS | title = Axoaxonic synaptogenesis in neonatal kitten spinal trigeminal nucleus | journal = Brain Research | volume = 138 | issue = 3 | pages = 534–7 | date = December 1977 | pmid = 616291 | doi = 10.1016/0006-8993(77)90689-8 | s2cid = 27050299 }} 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 released in the synaptic cleft, which can be observed in the micrographs. 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 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 and 27 days of age, there is another surge of axo-axonic synaptogenesis. Axo-axonic synapses are also observed in the solitary nucleus (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 terminals by the presynaptic adrenergic fibers, and are proposed to play a role in baroreflex.{{cite journal | vauthors = Chiba T, Doba N | title = Catecholaminergic axo-axonic synapses in the nucleus of the tractus solitarius (pars commissuralis) of the cat: possible relation to presynaptic regulation of baroreceptor reflexes | journal = Brain Research | volume = 102 | issue = 2 | pages = 255–65 | date = February 1976 | pmid = 1247885 | doi = 10.1016/0006-8993(76)90881-7 | s2cid = 21966627 }}

Axo-axonic synapses are found in the mammalian spinal reflex arc{{cite journal | vauthors = Goulding M, Bourane S, Garcia-Campmany L, Dalet A, Koch S | title = Inhibition downunder: an update from the spinal cord | journal = Current Opinion in Neurobiology | volume = 26 | pages = 161–6 | date = June 2014 | pmid = 24743058 | pmc = 4059017 | doi = 10.1016/j.conb.2014.03.006 | url = | series = SI: Inhibition: Synapses, Neurons and Circuits }}{{cite journal | vauthors = Araki T, Otani T | title = Response of single motoneurons to direct stimulation in toad's spinal cord | journal = Journal of Neurophysiology | volume = 18 | issue = 5 | pages = 472–85 | date = September 1955 | pmid = 13252436 | doi = 10.1152/jn.1955.18.5.472 }}{{cite journal | vauthors = Coombs JS, Curtis DR, Eccles JC | title = The generation of impulses in motoneurones | journal = The Journal of Physiology | volume = 139 | issue = 2 | pages = 232–49 | date = December 1957 | pmid = 13492210 | pmc = 1358726 | doi = 10.1113/jphysiol.1957.sp005888 }} and in Substantia gelatinosa of Rolando (SGR).{{cite journal | vauthors = Zhu CG, Sandri C, Akert K | title = Morphological identification of axo-axonic and dendro-dendritic synapses in the rat substantia gelatinosa | journal = Brain Research | volume = 230 | issue = 1–2 | pages = 25–40 | date = December 1981 | pmid = 7317779 | doi = 10.1016/0006-8993(81)90389-9 | s2cid = 32854329 }} 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.{{cite journal | vauthors = Conradi S | title = Axo-axonic synapses on cat spinal motoneurons | journal = Acta Societatis Medicorum Upsaliensis | volume = 73 | issue = 5–6 | pages = 239–42 | date = 1968 | pmid = 5734435 }} This seems to be a common mechanism in spinal cords, in which GABAergic interneurons inhibit presynaptic activity in sensory neurons and eventually control activity in motor neurons enabling selective control of muscles.{{cite journal | vauthors = Rudomin P | title = Presynaptic inhibition of muscle spindle and tendon organ afferents in the mammalian spinal cord | journal = Trends in Neurosciences | volume = 13 | issue = 12 | pages = 499–505 | date = December 1990 | pmid = 1703681 | doi = 10.1016/0166-2236(90)90084-N | s2cid = 4050785 }} 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.

Axo-axonic synapses are found in the lateral vestibular nucleus 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.{{cite journal | vauthors = Sotelo C, Palay SL | title = The fine structure of the later vestibular nucleus in the rat. II. Synaptic organization | journal = Brain Research | volume = 18 | issue = 1 | pages = 93–115 | date = February 1970 | pmid = 4313893 | doi = 10.1016/0006-8993(70)90459-2 }} 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 neural computation for the vestibular reflex in rats.

Axo-axonic synapses are found in the mauthner cells in goldfish.{{cite journal | vauthors = Robertson JD, Bodenheimer TS, Stage DE | title = The Ultrastructure of Mauthner Cell Synapses and Nodes in Goldfish Brains | journal = The Journal of Cell Biology | volume = 19 | issue = 1 | pages = 159–99 | date = October 1963 | pmid = 14069792 | pmc = 2106865 | doi = 10.1083/jcb.19.1.159 }}{{cite journal | vauthors = Nakajima Y | title = Fine structure of the synaptic endings on the Mauthner cell of the goldfish | journal = The Journal of Comparative Neurology | volume = 156 | issue = 4 | pages = 379–402 | date = August 1974 | pmid = 4137668 | doi = 10.1002/cne.901560402 | s2cid = 42394435 }} The axon hillock and initial axon segments of mauthner cells receive terminals from extremely fine unmyelinated 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 reflexes 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, 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.{{cite journal | vauthors = Bierman HS, Zottoli SJ, Hale ME | title = Evolution of the Mauthner axon cap | journal = Brain, Behavior and Evolution | volume = 73 | issue = 3 | pages = 174–87 | date = 2009 | pmid = 19494486 | doi = 10.1159/000222562 | s2cid = 25637965 }}

Inhibitory axo-axonic synapses are found in the crustacean neuromuscular junctions and have been widely studied in Crayfish.{{cite journal | vauthors = Pearce J, Govind CK | title = Reciprocal axo-axonal synapses between the common inhibitor and excitor motoneurons in crustacean limb muscles | journal = Journal of Neurocytology | volume = 22 | issue = 4 | pages = 259–65 | date = April 1993 | pmid = 8478645 | doi = 10.1007/BF01187124 | s2cid = 8541786 }} 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 neuromuscular junction 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 for controlled leg movements.

An example of the physiological role of axo-axonic synapses, which are formed by GABAergic inhibitory interneurons to the axons of granule cells, is in eliciting spontaneous seizures, which is a key symptom of Intractable Epilepsy.{{cite journal | vauthors = Sayin U, Osting S, Hagen J, Rutecki P, Sutula T | title = Spontaneous seizures and loss of axo-axonic and axo-somatic inhibition induced by repeated brief seizures in kindled rats | journal = The Journal of Neuroscience | volume = 23 | issue = 7 | pages = 2759–68 | date = April 2003 | pmid = 12684462 | pmc = 6742074 | doi = 10.1523/JNEUROSCI.23-07-02759.2003 }} The presynaptic inhibitory interneurons, which can be labeled by cholecystokinin and GAT-1, are found to modulate the granule cells's spike output. The same cells subsequently project excitatory mossy fibers to pyramidal neurons in the hippocampal CA3 region.

One of the two leading theories for the pathoetiology of schizophrenia is the glutamate theory. Glutamate is a well studied neurotransmitter for its role in learning and memory, and also in the brain development during prenatal 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 for the postsynaptic glutamatergic neurons.{{cite journal | vauthors = Howes O, McCutcheon R, Stone J | title = Glutamate and dopamine in schizophrenia: an update for the 21st century | journal = Journal of Psychopharmacology | volume = 29 | issue = 2 | pages = 97–115 | date = February 2015 | pmid = 25586400 | pmc = 4902122 | doi = 10.1177/0269881114563634 }} This mechanism is proposed to be a possible mechanism for glutamate dysfunction in observed schizophrenia.

A study on the spinal cord in mice suggests that the sensory Ig/Caspr4 complex is involved in the formation of axo-axonic synapses on proprioceptive afferents. These synapses are formed through projection of GABAergic interneurons on sensory neurons, 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 and the role of NB2 in synaptogenesis of axo-axonic type of synapses.{{cite journal | vauthors = Ashrafi S, Betley JN, Comer JD, Brenner-Morton S, Bar V, Shimoda Y, Watanabe K, Peles E, Jessell TM, Kaltschmidt JA | display-authors = 6 | title = Neuronal Ig/Caspr recognition promotes the formation of axoaxonic synapses in mouse spinal cord | language = en | journal = Neuron | volume = 81 | issue = 1 | pages = 120–9 | date = January 2014 | pmid = 24411736 | pmc = 3898991 | doi = 10.1016/j.neuron.2013.10.060 }}

• Synapse
• Synaptic plasticity
• Neural computation
• Dendrodendritic synapse

{{Reflist}}

{{refbegin|30em}}

• {{cite book | vauthors = Alford S, Schwartz E | date = 2009 | chapter = Presynaptic inhibition | pages = 1001–1006 | title = Encyclopedia of Neuroscience | doi = 10.1016/B978-008045046-9.00814-7 | isbn = 9780080450469 }}
• {{cite book | vauthors = Bennett MR | title = History of the Synapse | publisher = CRC Press | date = 11 October 2001 | isbn = 9781482284171 | url = https://books.google.com/books?id=m0lZDwAAQBAJ&pg=PP1 }}
• {{cite book | vauthors = Eccles JC | url = https://books.google.com/books?id=MzMEAwAAQBAJ&dq=synapse&pg=PP1 | title = The Physiology of Synapses | publisher = Academic Press | date = 22 October 2013 |isbn = 9781483226064}}
• {{cite book | veditors = Kandel ER | url = https://neurology.mhmedical.com/book.aspx?bookID=1049 | title = Principles of Neural Science | edition = 5th | location = New York | publisher = McGraw-Hill | date = 2013 }}
• {{cite book | veditors = Roberts A, Bush BM | title = Neurones without impulses: their significance for vertebrate and invertebrate nervous systems. | publisher = Cambridge University Press | date = 5 February 1981 | url = https://www.cambridge.org/us/academic/subjects/life-sciences/neuroscience/neurones-without-impulses-their-significance-vertebrate-and-invertebrate-nervous-systems?format=PB&isbn=9780521299350 }}
• {{cite journal | vauthors = DeFelipe J, Jones EG | title = Santiago Ramón y Cajal and methods in neurohistology | journal = Trends in Neurosciences | volume = 15 | issue = 7 | pages = 237–46 | date = July 1992 | pmid = 1381115 | doi = 10.1016/0166-2236(92)90057-f | s2cid = 44572164 }}
• {{cite journal | vauthors = Eccles JC | title = The mechanism of synaptic transmission | journal = Ergebnisse der Physiologie, Biologischen Chemie und Experimentellen Pharmakologie | volume = 51 | pages = 299–430 | date = 1961 | pmid = 13889060 | doi = 10.1007/BF02269100| s2cid = 84195141 }}
• {{cite journal | vauthors = Mozzachiodi R, Byrne JH | title = More than synaptic plasticity: role of nonsynaptic plasticity in learning and memory | journal = Trends in Neurosciences | volume = 33 | issue = 1 | pages = 17–26 | date = January 2010 | pmid = 19889466 | pmc = 2815214 | doi = 10.1016/j.tins.2009.10.001 }}
• {{cite journal | vauthors = Vitten H, Isaacson JS | title = Synaptic transmission: exciting times for presynaptic receptors | journal = Current Biology | volume = 11 | issue = 17 | pages = R695–7 | date = September 2001 | pmid = 11553342 | doi = 10.1016/s0960-9822(01)00411-0 | doi-access = free | bibcode = 2001CBio...11.R695V }}
• {{cite journal | vauthors = Zhou ZJ, Lee S | title = Synaptic physiology of direction selectivity in the retina | journal = The Journal of Physiology | volume = 586 | issue = 18 | pages = 4371–6 | date = September 2008 | pmid = 18617561 | pmc = 2614022 | doi = 10.1113/jphysiol.2008.159020 }}

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Category:Neurohistology

Category:Neuroscience

Category:Neural synapse