Axo-axonic synapse

An axo-axonic synapse is a type of synapse, formed by one neuron projecting its axon terminals onto another neuron's axon.
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 in the postsynaptic neuron. Instead, it affects the probability of neurotransmitter 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 in achieving a specialized neural computation.
Axo-axonic synapses are found throughout the central nervous system, including in the hippocampus, cerebral cortex and striatum in mammals; in the neuro-muscular junctions in crustaceans; and in the visual circuitry in dipterans. Axo-axonic synapses can induce either inhibitory or excitatory effects in the postsynaptic neuron. A classic example of the role of axo-axonic synapses is causing inhibitory effects on motoneurons in the spinal-somatic reflex arc. This phenomenon is known as presynaptic-inhibition.

Background

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. 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, and the suffix represents the location where the synapse is formed on the postsynaptic neuron. 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.
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 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.

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 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 of cats and pigeons, in the lateral geniculate nucleus of monkeys, in the olfactory bulb 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 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 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.

Function

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

Cerebellar cortex

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. 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. Network-level study revealed that the granule cells which, through their parallel fibers, activate Purkinje cells, also activate the basket cells, which subsequently inhibit the effect of Purkinje cells on the downstream network.

Cerebral cortex

Axo-axonic synapses are found In the visual cortex 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 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. 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, which aids olfaction. 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. 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.

Basal ganglia

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. 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 projecting onto the axons of glutamatergic cortico-striatal fibers in the rat striatum.

Brainstem

Axo-axonic synapses are found in the spinal trigeminal nucleus in the brainstem. 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 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.