Neural facilitation

Last updated October 26, 2023

Neural facilitation, also known as paired-pulse facilitation (PPF), is a phenomenon in neuroscience in which postsynaptic potentials (PSPs) (EPPs, EPSPs or IPSPs) evoked by an impulse are increased when that impulse closely follows a prior impulse. PPF is thus a form of short-term synaptic plasticity. The mechanisms underlying neural facilitation are exclusively pre-synaptic; broadly speaking, PPF arises due to increased presynaptic Ca²⁺
concentration leading to a greater release of neurotransmitter-containing synaptic vesicles.^[1] Neural facilitation may be involved in several neuronal tasks, including simple learning, information processing,^[2] and sound-source localization.^[3]

Mechanisms

Overview

Ca²⁺
plays a significant role in transmitting signals at chemical synapses. Voltage-gated Ca²⁺
channels are located within the presynaptic terminal. When an action potential invades the presynaptic membrane, these channels open and Ca²⁺
enters. A higher concentration of Ca²⁺
enables synaptic vesicles to fuse to the presynaptic membrane and release their contents (neurotransmitters) into the synaptic cleft to ultimately contact receptors in the postsynaptic membrane. The amount of neurotransmitter released is correlated with the amount of Ca²⁺
influx. Therefore, short-term facilitation (STF) results from a build up of Ca²⁺
within the presynaptic terminal when action potentials propagate close together in time.^[4]

Facilitation of excitatory post-synaptic current (EPSC) can be quantified as a ratio of subsequent EPSC strengths. Each EPSC is triggered by pre-synaptic calcium concentrations and can be approximated by:

EPSC = k([Ca²⁺
]_presynaptic)⁴ = k([Ca²⁺
]_rest + [Ca²⁺
]_influx + [Ca²⁺
]_residual)⁴

Where k is a constant.

Facilitation = EPSC₂ / EPSC₁ = (1 + [Ca²⁺
]_residual / [Ca²⁺
]_influx)⁴ - 1

Experimental evidence

Early experiments by Del Castillo & Katz in 1954 and Dudel & Kuffler in 1968 showed that facilitation was possible at the neuromuscular junction even if transmitter release does not occur, indicating that facilitation is an exclusively presynaptic phenomenon.^[5]^[6]

Katz and Miledi proposed the residual Ca²⁺
hypothesis. They attributed the increase in neurotransmitter release to residual or accumulated Ca²⁺
("active calcium") within the axon membrane that remains attached to the membrane's inner surface.^[7] Katz and Miledi manipulated the Ca²⁺
concentration within the presynaptic membrane to determine whether or not residual Ca²⁺
remaining within the terminal after the first impulse caused an increase in neurotransmitter release following the second stimulus.

During the first nerve impulse, Ca²⁺
concentration was either significantly below or nearing that of the second impulse. When Ca²⁺
concentration was approaching that of the second impulse, facilitation was increased. In this first experiment, stimuli were presented in intervals of 100 ms between the first and second stimuli. An absolute refractory period was reached when intervals were about 10 ms apart.

To examine facilitation during shorter intervals, Katz and Miledi directly applied brief depolarizing stimuli to nerve endings. When increasing the depolarizing stimulus from 1-2 ms, neurotransmitter release greatly increased due to accumulation of active Ca²⁺
. Therefore, the degree of facilitation depends on the amount of active Ca²⁺
, which is determined by the reduction in Ca²⁺
conductance over time as well as the amount of removed from axon terminals after the first stimulus. Facilitation is greatest when the impulses are closest together because Ca²⁺
conductance would not return to baseline prior to the second stimulus. Therefore, both Ca²⁺
conductance and accumulated Ca²⁺
would be greater for the second impulse when presented shortly after the first.

In the Calyx of Held synapse, short term facilitation (STF) has been shown to result from the binding of residual Ca²⁺
to neuronal Ca²⁺
sensor 1 (NCS1). Conversely, STF has been shown to decrease when Ca²⁺
chelators are added to the synapse (causing chelation) which reduce residual Ca²⁺
. Therefore, "active Ca²⁺
" plays a significant role in neural facilitation.^[8]

In the synapse between Purkinje cells, short-term facilitation has been shown to be entirely mediated by the facilitation of Ca²⁺
currents through the voltage-dependent calcium channels.^[9]

Relation to other forms of short-term synaptic plasticity

Augmentation and potentiation

Short-term synaptic enhancement is often differentiated into categories of facilitation, augmentation , and potentiation (also referred to as post-tetanic potentiation or PTP).^[1]^[10] These three processes are often differentiated by their time scales: facilitation usually lasts for tens of milliseconds, while augmentation acts on a time scale on the order of seconds and potentiation has a time course of tens of seconds to minutes. All three effects increase the probability of neurotransmitter release from the presynaptic membrane, but the underlying mechanism is different for each. Paired-pulse facilitation is caused by the presence of residual Ca²⁺
, augmentation likely arises due to increased action of the presynaptic protein munc-13, and post-tetanic potentiation is mediated by presynaptic activation of protein kinases.^[4] The type of synaptic enhancement seen in a given cell is also related to variant dynamics of Ca²⁺
removal, which is in turn dependent upon the type of stimuli; a single action potential leads to facilitation, while a short tetanus generally causes augmentation and a longer tetanus leads to potentiation.^[1]

Short-term depression (STD)

Short-term depression (STD) operates in the opposite direction of facilitation, decreasing the amplitude of PSPs. STD occurs due to a decrease in the readily releasable pool of vesicles (RRP) as a result of frequent stimulation. The inactivation of presynaptic Ca²⁺
channels after repeated action potentials also contributes to STD.^[8] Depression and facilitation interact to create short-term plastic changes within neurons, and this interaction is called the dual-process theory of plasticity. Basic models present these effects as additive, with the sum creating the net plastic change (facilitation - depression = net change). However, it has been shown that depression occurs earlier on in the stimulus-response pathway than facilitation, and therefore plays into the expression of facilitation.^[11] Many synapses exhibit properties of both facilitation and depression. In general, however, synapses with low initial probability of vesicle release are more likely to exhibit facilitation, and synapses with high probability of initial vesicle release are more likely to exhibit depression.^[3]

Relation to information transmission

Synaptic filtering

Because the probability of vesicle release is activity-dependent, synapses can act as dynamic filters for information transmission.^[3] Synapses with a low initial probability of vesicle release act as high-pass filters: because the release probability is low, a higher-frequency signal is needed to trigger release, and the synapse thus selectively responds to high-frequency signals. Likewise, synapses with high initial release probabilities serve as low-pass filters, responding to lower-frequency signals. Synapses with an intermediate probability of release act as band-pass filters that selectively respond to a specific range of frequencies. These filtering characteristics may be affected by a variety of factors, including both PPD and PPF, as well as chemical neuromodulators. In particular, because synapses with low release probabilities are more likely to experience facilitation than depression, high-pass filters are often converted to band-pass filters. Likewise, because synapses with high initial release probabilities are more likely to undergo depression than facilitation, it is common for low-pass filters to become band-pass filters, as well. Neuromodulators, meanwhile, may affect these short-term plasticities. In synapses with intermediate release probabilities, properties of the individual synapse will determine how the synapse changes in response to stimuli. These changes in filtration affect information transmission and encoding in response to repeated stimuli.^[3]

Sound-source localization

In humans, sound localization is primarily accomplished using information about how the intensity and timing of a sound vary between each ear. Neuronal computations involving these interaurual intensity differences (IIDs) and interaural time differences (ITDs) are typically carried out in different pathways in the brain.^[12] Short-term plasticity likely assists in differentiating between these two pathways: short-term facilitation dominates in intensity pathways, while short-term depression dominates in temporal pathways. These different types of short-term plasticity allow for different kinds of information filtration, thus contributing to the division of the two kinds of information into distinct processing streams.

The filtering capabilities of short-term plasticity may also assist with encoding information related to amplitude modulation (AM).^[12] Short-term depression can dynamically adjust the gain on high-frequency inputs, and may thus allow for an expanded high-frequency range for AM. A mixture of facilitation and depression may also assist in AM coding by leading to rate filtering.

Related Research Articles

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, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

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 neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

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.

In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.

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.

Metaplasticity is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of individual synapses. However this new form referred to the plasticity of the plasticity itself, thus the term meta-plasticity. The idea is that the synapse's previous history of activity determines its current plasticity. This may play a role in some of the underlying mechanisms thought to be important in memory and learning such as long-term potentiation (LTP), long-term depression (LTD) and so forth. These mechanisms depend on current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamines, and the pool of hormones affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed metaplasticity. There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science. Most research of this type is done via cultured hippocampus cells or hippocampal slices.

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.

Augmentation is one of four components of short-term synaptic plasticity that increases the probability of releasing synaptic vesicles during and after repetitive stimulation such that

<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 in order to transmit those impulses to other neurons, muscle cells or glands. In the central nervous system, most presynaptic terminals are actually 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.

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

Post-tetanic potentiation (PTP) is a form of synaptic plasticity which is short-lived and results in increased frequency of miniature excitatory postsynaptic potentials (mEPSPs) or currents (EPSCs) with no effect on amplitude in the spontaneous postsynaptic potential. It usually lasts in the range of several minutes. PTPs are observed when synapses are stimulated with repetitive (tetanic) pulses, by means of prolonged trains of stimuli applied at high frequencies.

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.

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