Multivesicular release

Last updated July 02, 2024

Communication between neurons happens primarily through chemical neurotransmission at the synapse. Neurotransmitters are packaged into synaptic vesicles for release from the presynaptic cell into the synapse, from where they diffuse and can bind to postsynaptic receptors. While most presynaptic cells are historically thought to release one vesicle at a time per active site, more recent research has pointed towards the possibility of multiple vesicles being released from the same active site (multivesicular release; MVR) in response to an action potential.

Basics of neuronal signaling

In the nervous system there are primarily two ways of propagating signals. By far the most common method of intracellular signal propagation is the action potential.^[1] The dendrites of neurons contain ionotropic (aka ligand-gated ion channel) and metabotropic neurotransmitter receptors that bind chemical neurotransmitters. At ionotropic receptors, these chemical neurotransmitters cause quick changes in ion flux into or out of the cell. The resulting internal voltage change in the dendrites is propagated towards the cell body and axon hillock, where a large concentration of voltage-gated ion channels typically exists. If some voltage threshold is met, voltage gated sodium channels open up, letting in a critical charge of sodium, and the positive current propagates down the axon towards the presynaptic axon terminal. This action potential leads to neurotransmitter vesicular release at in this terminal.

While action potentials are the typical means of signal propagation in the nervous system, some sensory neurons use graded potentials to trigger vesicular release. These cells are typically short enough that regenerative action potentials aren't needed to cause a large enough voltage change at the presynaptic terminal. For example, photoreceptor cells in the eye produce graded potentials in response to light, and these graded potentials can directly lead to neurotransmitter release.^[2]

Univesicular release

Most presynaptic terminals release small numbers of neurotransmitter containing vesicles even when action potentials are not present. This is stochastic and the probability of release (Pr) can be modified by numerous factors including the presence and speed of an action potential.^[3] These vesicles are released at synaptic active zones, areas of the axon terminal that have all of the machinery and conditions necessary to specialize in vesicle fusion with the plasma membrane. Until relatively recently, the prevailing hypothesis was that only one vesicle at a time is released from these active zones.^[4] However, research over the past several decades has added support for an additional mechanism of neurotransmitter vesicle release.

Multivesicular release hypothesis

While univesicular release is still believed to make up a substantial portion of transmitter release events, large fluctuations in postsynaptic cell current measurements and high transmitter concentration in some synapses have led to the hypothesis that multiple vesicles can be released per active zone with each action potential. Since vesicular release happens on the scale of microseconds, it has been difficult to capture direct electron microscopic evidence of this phenomenon. There is however considerable functional data that supports MVR throughout much of the brain and sensory neuron synapses.^[5]

Effects on signaling

MVR is thought to affect signal strength in postsynaptic neurons that typically have low receptor occupancy; this number can vary widely throughout the nervous system. This means that for however many receptors are found on a postsynaptic cell in the area of presynaptic cell vesicle release, only a small number of them would typically be occupied by neurotransmitter released from one vesicle (each vesicle can contain up to approximately 10,000 molecules of neurotransmitter).^[6] MVR increases the likelihood that an action potential in a presynaptic cell will result in a postsynaptic cell chance in action potential likelihood. This could be either more or fewer action potentials, depending upon if the neurotransmitter / receptor combo is excitatory or inhibitory.^[7]

Physiological effects

MVR likely plays a substantial role in hippocampal signaling and memory. MVR exists in both near-synchronous (mulitiple vesicles released within tens of microseconds) and desynchronous (multiple vesicles released over a somewhat longer timescale). These different types of MVR can have differential effects on the post-synaptic neuron. Near-synchronous MVR leads to a fast onset and decline of synapse neurotransmitter levels as the molecules diffuse away or are taken up by neurotransmitter reuptake transporters (e.g. synapse glutamate transporters in neurons and glia. In the hippocampus, AMPA receptors that bind glutamate released in this manner produce a relatively large positive change in postsynaptic dendrite current (also called the excitatory postsynaptic current; EPSC). When the same receptors are exposed to de-synchronous MVR, which can lead to the same level of synaptic neurotransmitter but over a much longer timescale, the AMPA receptors can become desensitized, which leads to a smaller EPSC. This desensitization can reduce AMPA receptor availability and contribute to short-term depression, one of the fundamental mechanisms of learning and memory in hippocampal circuits.^[5]

NMDA receptors are one of the other main types of glutamatergic receptors in the hippocampus. NMDA receptors allow calcium into the postsynaptic cell when they bind glutamate. Previous work in the hippocampus has shown that the response to stimulation of a single axon can be highly variable. Unlike earlier electrophysiology studies that studied postsynaptic currents due to calcium influx at multiple synapses, improved experimental techniques have allowed the isolation and study of individual synapses. This revolution in experimental technique has helped answer the question if the variable response to stimulation is due to UVR at a varying number of synapses, or to MVR at a single synapse. Individual synapse studies have found that after presynaptic axon stimulation, the postsynaptic NMDA-mediated calcium influx is highly variable, supporting the hypothesis that MVR can play a role at these synapses as well.^[5]

One of the main benefits of MVR is thought to be the maintenance of information fidelity. Many sensory synapses take advantage of MVR to regulate firing duration and frequency, and to ensure reliable and sustained postsynaptic firing at high frequencies. Small changes in postsynaptic current are less likely to affect action potential generation than large ones are, hence the "information" held within presynaptic cell activity is less likely to make it farther downstream in the circuit. Since MVR results in release of more neurotransmitter, the changes in postsynaptic current tend to be larger, and information is more likely to be reliably propagated downstream.^[8]

MVR is also thought to participate in vesicular release at ribbon synapses that are prominent in the sensory nervous system.^[5] Presynaptic cells at primary synapses in the sensory nervous system typically are smaller than many other neurons, and can rely on graded potentials in the cells to reliably trigger neurotransmitter release at their synaptic terminals.^[9] These graded potentials can last for several seconds and result in the release of thousands of neurotransmitter vesicles from a neuron. These synapses have specialized ribbon-like protein structures that can bind thousands of vesicles at a time, and MVR is capable of modulating a high level of vesicular release to transmit meaningful changes in sensation to the next sensory neuron downstream.

The balance between UVR and MVR is not necessarily static at any given synapse, as it can change over time. During development, many synapses undergo activity dependent pruning.^[10] In general, those that are less active are most likely to be removed from the nervous system compared to those that are more active. This phenomenon has been observed in several brain areas, including the cerebellum. In this structure, many climbing fibers synapse onto individual Purkinje neurons. The climbing fiber axon terminals with the highest level of MVR versus UVR tend to cause the largest change in Purkinje neuron calcium influx, and these synapses are typically retained in the developing circuitry compared to those that have a lower level of calcium influx.^[5] In the developing auditory system, MVR becomes less prominent as the Calyx of Held synapses mature and change shape. At this location, these shape changes increase action potential speed and decrease Pr. The decrease in Pr and MVR reduces synaptic glutamate and AMPA receptor desensitization, leading to a higher frequency of action potentials in the postsynaptic neuron. These maturation induced changes in MVR are also likely relevant at other locations in the developing nervous system.

Related Research Articles

Within a nervous system, a neuron, neurone, or nerve cell is an electrically excitable cell that fires electric signals called action potentials across a neural network. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap.

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 system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

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 flow of positively charged ions into the postsynaptic cell, is a result of opening ligand-gated ion channels. These are the opposite of inhibitory postsynaptic potentials (IPSPs), which usually result from the flow of negative ions into the cell or positive ions out of the cell. EPSPs can also result from a decrease in outgoing positive charges, while IPSPs are sometimes caused by an increase in positive charge outflow. The flow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC).

In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

Schaffer collaterals are axon collaterals given off by CA3 pyramidal cells in the hippocampus. These collaterals project to area CA1 of the hippocampus and are an integral part of memory formation and the emotional network of the Papez circuit, and of the hippocampal trisynaptic loop. It is one of the most studied synapses in the world and named after the Hungarian anatomist-neurologist Károly Schaffer.

Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

<span class="mw-page-title-main">Synaptic potential</span> Potential difference across the postsynaptic membrane

Synaptic potential refers to the potential difference across the postsynaptic membrane that results from the action of neurotransmitters at a neuronal synapse. In other words, it is the “incoming” signal that a neuron receives. There are two forms of synaptic potential: excitatory and inhibitory. The type of potential produced depends on both the postsynaptic receptor, more specifically the changes in conductance of ion channels in the post synaptic membrane, and the nature of the released neurotransmitter. Excitatory post-synaptic potentials (EPSPs) depolarize the membrane and move the potential closer to the threshold for an action potential to be generated. Inhibitory postsynaptic potentials (IPSPs) hyperpolarize the membrane and move the potential farther away from the threshold, decreasing the likelihood of an action potential occurring. The Excitatory Post Synaptic potential is most likely going to be carried out by the neurotransmitters glutamate and acetylcholine, while the Inhibitory post synaptic potential will most likely be carried out by the neurotransmitters gamma-aminobutyric acid (GABA) and glycine. In order to depolarize a neuron enough to cause an action potential, there must be enough EPSPs to both depolarize the postsynaptic membrane from its resting membrane potential to its threshold and counterbalance the concurrent IPSPs that hyperpolarize the membrane. As an example, consider a neuron with a resting membrane potential of -70 mV (millivolts) and a threshold of -50 mV. It will need to be raised 20 mV in order to pass the threshold and fire an action potential. The neuron will account for all the many incoming excitatory and inhibitory signals via summative neural integration, and if the result is an increase of 20 mV or more, an action potential will occur.

The Calyx of Held is a particularly large synapse in the mammalian auditory central nervous system, so named after Hans Held who first described it in his 1893 article Die centrale Gehörleitung because of its resemblance to the calyx of a flower. Globular bushy cells in the anteroventral cochlear nucleus (AVCN) send axons to the contralateral medial nucleus of the trapezoid body (MNTB), where they synapse via these calyces on MNTB principal cells. These principal cells then project to the ipsilateral lateral superior olive (LSO), where they inhibit postsynaptic neurons and provide a basis for interaural level detection (ILD), required for high frequency sound localization. This synapse has been described as the largest in the brain.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca²⁺ signaling, although recent research has questioned the role of Ca²⁺ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

<span class="mw-page-title-main">Summation (neurophysiology)</span>

Summation, which includes both spatial summation and temporal summation, is the process that determines whether or not an action potential will be generated by the combined effects of excitatory and inhibitory signals, both from multiple simultaneous inputs, and from repeated inputs. Depending on the sum total of many individual inputs, summation may or may not reach the threshold voltage to trigger an action potential.

Axon terminals are distal terminations of the branches of an axon. An axon, also called a nerve fiber, is a long, slender projection of a nerve cell that conducts electrical impulses called action potentials away from the neuron's cell body to transmit those impulses to other neurons, muscle cells, or glands. Most presynaptic terminals in the central nervous system are formed along the axons, not at their ends.

Cellular neuroscience is a branch of neuroscience concerned with the study of neurons at a cellular level. This includes morphology and physiological properties of single neurons. Several techniques such as intracellular recording, patch-clamp, and voltage-clamp technique, pharmacology, confocal imaging, molecular biology, two photon laser scanning microscopy and Ca²⁺ imaging have been used to study activity at the cellular level. Cellular neuroscience examines the various types of neurons, the functions of different neurons, the influence of neurons upon each other, and how neurons work together.

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

In neuroscience, synaptic scaling is a form of homeostatic plasticity, in which the brain responds to chronically elevated activity in a neural circuit with negative feedback, allowing individual neurons to reduce their overall action potential firing rate. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections by decreasing the strength of each synapse by the same factor, so that the relative synaptic weighting of each synapse is preserved.

Synaptic fatigue, or short-term synaptic depression, is an activity-dependent form of short term synaptic plasticity that results in the temporary inability of neurons to fire and therefore transmit an input signal. It is thought to be a form of negative feedback in order to physiologically control particular forms of nervous system activity.

Neurotransmitters are released into a synapse in packaged vesicles called quanta. One quantum generates a miniature end plate potential (MEPP) which is the smallest amount of stimulation that one neuron can send to another neuron. Quantal release is the mechanism by which most traditional endogenous neurotransmitters are transmitted throughout the body. The aggregate sum of many MEPPs is an end plate potential (EPP). A normal end plate potential usually causes the postsynaptic neuron to reach its threshold of excitation and elicit an action potential. Electrical synapses do not use quantal neurotransmitter release and instead use gap junctions between neurons to send current flows between neurons. The goal of any synapse is to produce either an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP), which generate or repress the expression, respectively, of an action potential in the postsynaptic neuron. It is estimated that an action potential will trigger the release of approximately 20% of an axon terminal's neurotransmitter load.

References

↑ Grider, Michael H.; Jessu, Rishita; Kabir, Rian (2023). "Physiology, Action Potential". StatPearls. StatPearls Publishing. PMID 30844170.
↑ Henley, Casey (1 January 2021). "Vision: The Retina".
↑ Branco, Tiago; Staras, Kevin (May 2009). "The probability of neurotransmitter release: variability and feedback control at single synapses". Nature Reviews Neuroscience. 10 (5): 373–383. doi:10.1038/nrn2634.
↑ Redman, S (January 1990). "Quantal analysis of synaptic potentials in neurons of the central nervous system". Physiological Reviews. 70 (1): 165–198. doi:10.1152/physrev.1990.70.1.165. PMID 2404288.
1 2 3 4 5 Rudolph, Stephanie; Tsai, Ming-Chi; von Gersdorff, Henrique; Wadiche, Jacques I. (July 2015). "The ubiquitous nature of multivesicular release". Trends in Neurosciences. 38 (7): 428–438. doi:10.1016/j.tins.2015.05.008. PMC 4495900 . PMID 26100141.
↑ "Mechanisms of Neurotransmitter Release (Section 1, Chapter 5) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston". nba.uth.tmc.edu.
↑ Henley, Casey (1 January 2021). "Postsynaptic Potentials".
↑ Chanaday, Natali L.; Kavalali, Ege T. (August 2018). "Presynaptic origins of distinct modes of neurotransmitter release". Current Opinion in Neurobiology. 51: 119–126. doi:10.1016/j.conb.2018.03.005. PMC 6066415 . PMID 29597140.
↑ "Visual Processing: Eye and Retina (Section 2, Chapter 14) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston". nba.uth.tmc.edu.
↑ Sakai, Jill (14 July 2020). "How synaptic pruning shapes neural wiring during development and, possibly, in disease". Proceedings of the National Academy of Sciences. 117 (28): 16096–16099. doi: 10.1073/pnas.2010281117 . PMID 32581125.

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[1] Grider, Michael H.; Jessu, Rishita; Kabir, Rian (2023). "Physiology, Action Potential". StatPearls. StatPearls Publishing. PMID 30844170.

[2] Henley, Casey (1 January 2021). "Vision: The Retina".

[3] Branco, Tiago; Staras, Kevin (May 2009). "The probability of neurotransmitter release: variability and feedback control at single synapses". Nature Reviews Neuroscience. 10 (5): 373–383. doi:10.1038/nrn2634.

[4] Redman, S (January 1990). "Quantal analysis of synaptic potentials in neurons of the central nervous system". Physiological Reviews. 70 (1): 165–198. doi:10.1152/physrev.1990.70.1.165. PMID 2404288.

[sr-5] 1 2 3 4 5 Rudolph, Stephanie; Tsai, Ming-Chi; von Gersdorff, Henrique; Wadiche, Jacques I. (July 2015). "The ubiquitous nature of multivesicular release". Trends in Neurosciences. 38 (7): 428–438. doi:10.1016/j.tins.2015.05.008. PMC 4495900 . PMID 26100141.

[6] "Mechanisms of Neurotransmitter Release (Section 1, Chapter 5) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston". nba.uth.tmc.edu.

[7] Henley, Casey (1 January 2021). "Postsynaptic Potentials".

[8] Chanaday, Natali L.; Kavalali, Ege T. (August 2018). "Presynaptic origins of distinct modes of neurotransmitter release". Current Opinion in Neurobiology. 51: 119–126. doi:10.1016/j.conb.2018.03.005. PMC 6066415 . PMID 29597140.

[9] "Visual Processing: Eye and Retina (Section 2, Chapter 14) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston". nba.uth.tmc.edu.

[10] Sakai, Jill (14 July 2020). "How synaptic pruning shapes neural wiring during development and, possibly, in disease". Proceedings of the National Academy of Sciences. 117 (28): 16096–16099. doi: 10.1073/pnas.2010281117 . PMID 32581125.

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