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The ribbon synapse is a type of neuronal synapse characterized by the presence of an electron-dense structure, the synaptic ribbon, that holds Synaptic vesicle close to the active zone. It is characterized by a tight vesicle-calcium channel coupling that promotes rapid neurotransmitter release and sustained signal transmission. Ribbon synapses undergo a cycle of exocytosis and endocytosis in response to graded changes of membrane potential. It has been proposed that most ribbon synapses undergo a special type of exocytosis based on coordinated multivesicular release. This interpretation has recently been questioned at the inner hair cell ribbon synapse, where it has been instead proposed that exocytosis is described by uniquantal (i.e., univesicular) release shaped by a flickering vesicle fusion pore.
These unique features specialize the ribbon synapse to enable extremely fast, precise and sustained neurotransmission, which is critical for the perception of complex senses such as vision and hearing. Ribbon synapses are found in retinal photoreceptor cells, vestibular organ receptors, , retinal bipolar cells, and .
The synaptic ribbon is a unique structure at the active zone of the synapse. It is positioned several nanometers away from the pre-synaptic membrane and tethers 100 or more synaptic vesicles. Each pre-synaptic cell can have from 10 to 100 ribbons tethered at the membrane, or a total number of 1000–10000 vesicles in close proximity to . The ribbon synapse was first identified in the retina as a thin, ribbon-like presynaptic projection surrounded by a halo of vesicles using transmission electron microscopy in the 1950s, as the technique was gaining mainstream usage.
Postsynaptic structures differ for cochlear cells and photoreceptor cells. Hair cells is capable of one action potential propagation for one vesicle release. One vesicle release from the presynaptic hair cell onto the postsynaptic bouton is enough to create an action potential in the auditory afferent cells. Photoreceptors allow one vesicle release for many action potential propagation. The rod terminal and cone ribbon synapse of the photoreceptors have horizontal synaptic spines expressing AMPA receptors with additional bipolar dendrites exhibiting the mGluR6 receptors. These structures allow for the binding of multiple molecules of glutamate, allowing for the propagation of many action potentials.
Several proteins of the synaptic ribbon have also been found to be associated with conventional synapses. RIM (Rab3-interacting proteins) is a GTPase expressed on synaptic vesicles that is important in priming synaptic vesicles. Immunostaining has revealed the presence of KIF3A, a component of the kinesin II motor complex whose function is still unknown. The presynaptic cytomatrix proteins Bassoon and PCLO are both expressed at photoreceptor ribbons, but Piccolo is only expressed at retinal bipolar synaptic ribbons. Bassoon is responsible for attaching itself to the base of the synaptic ribbons and subsequently anchoring the synaptic ribbons. The function of Piccolo is unknown. Also important is the filaments that tether the vesicles to the ribbon synapse. These are shed during high rates of exocytosis. The only unique protein associated with the synaptic ribbon is RIBEYE, first identified in purified synaptic ribbon from bovine retina. RIBEYE is encoded in vertebrate genomes as an alternative transcript of the CtBP2 gene. During chicken and human retinal development, RIBEYE is expressed in photoreceptor and bipolar cell retinal neurons. It is found to be a part of all vertebrate synaptic ribbons in ribbon synapses and is the central portion of ribbon synapses. RIBEYE interactions are required to form a scaffold formation protein of the synaptic ribbon.
There has been a significant amount of research into the pre-synaptic cytomatrix protein Bassoon, which is a multi-domain scaffolding protein universally expressed at synapses in the central nervous system. Mutations in Bassoon have been shown to result in decreased synaptic transmission. However, the underlying mechanisms behind this observed phenomenon are not fully understood and are currently being investigated. It has been observed that in the retina of Bassoon-mutant mice, photoreceptor ribbon synapses are not anchored to pre-synaptic active zones during photoreceptor synaptogenesis. The photoreceptor ribbon synapses are observed to be free floating in the cytoplasm of the photoreceptor terminals. These observations have led to the conclusion that Bassoon plays a critical role in the formation of the photoreceptor ribbon synapse.
Information is conveyed from photoreceptor cells to bipolar cells via the release of the neurotransmitter glutamate at the ribbon synapse. Conventional neurons encode information by changes in the rate of action potentials, but for complex senses like vision, this is not sufficient. Ribbon synapses enable neurons to transmit light signals over a dynamic range of several orders of magnitude in intensity. This is achieved by encoding intensity changes in tonic rate of transmitter release which requires the release of several hundred to several thousand synaptic vesicles per second.
To accomplish this level of performance, the sensory neurons of the eye maintain large pools of fast releasable vesicles that are equipped with ribbon synapses. This enables the cell to exocytose hundreds of vesicles per second, greatly exceeding the rate of neurons without the specialized ribbon synapse.
The current hypothesis of calcium-dependent exocytosis at retinal ribbon synapses suggests that the ribbon accommodates a reservoir of primed releasable vesicles. The vesicles that are in closest contact with the presynaptic plasma membrane at the base of the ribbon constitute the small, rapidly releasable pool of vesicles, whereas the remaining vesicles tethered to the ribbon constitute the large, readily (slower) releasable pool. These regularly aligned rows of synaptic vesicles tethered to either side of the ribbon along with the expression of the kinesin motor protein KIF3A at retinal ribbon synapses can move vesicles like a conveyor belt to the docking/release site at the ribbon base.
The bipolar cell active zone of the ribbon synapse can release neurotransmitter continuously for hundreds of milliseconds during strong stimulation. This release of neurotransmitters occurs in two kinetically distinct phases: a small fast pool where about twenty percent of the total is released in about 1 millisecond, and a large sustained pool where the remaining components are released over hundreds of milliseconds. The existence of correspondence between the pool of tethered vesicles and the pool for sustained release in the rods and bipolar cells of the ribbon reveals that the ribbon may serve as a platform where the vesicles can be primed to allow sustained release of neurotransmitters. This large size of the sustained large component is what separates the ribbon synapse active zones from those of conventional neurons where sustained release is small in comparison. Once the presynaptic vesicles have been depleted, the bipolar cell's releasable pool requires several seconds to refill with the help of ATP hydrolysis.
In studies of retinal genetic coding of laboratory mice, several mutated ribbon synapse associated voltage-gated L-type calcium channel auxiliary subunits were shown to be associated with dysfunctional rod and cone activity and information transmission. Mice were shown to express significantly reduced scotopic vision, and further research has shown the dysregulation of calcium homeostasis may have a significant role in rod photoreceptor degradation and death.
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