Synaptic fatigue
Encyclopedia
Synaptic fatigue, or short-term synaptic depression, is an activity-dependent form of short-term plasticity
that affects neuronal efficacy and results in the temporary inability 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. Synaptic fatigue involves the temporary inhibition of neurons
due to constant and persistent stimulation, where the fatigue effects are generally dependent upon the type and frequency of stimuli present. The underlying cause of fatigue on the synapse is temporary depletion of synaptic vesicles
that house neurotransmitters
in the presynaptic cell. The neurotransmitters are released to propagate the signal to the postsynaptic cell. It has also been hypothesized that synaptic fatigue could be a result of postsynaptic receptor desensitization or changes in postsynaptic passive conductance, but recent evidence has suggested that it is primarily a presynaptic phenomenon.
allow for signal transmission by a presynaptic cell releasing neurotransmitters into the synapse to bind to receptors on a postsynaptic cell. These neurotransmitters are synthesized in the presynaptic cell and housed in vesicles until released. Once neurotransmitters are released into the synaptic cleft and a signal is relayed, re-uptake
begins which is the process of transport proteins clearing out the neurotransmitters from the synapse and recycling them in order to allow for a new signal to be propagated. If stimulation is occurring at a high enough frequency and with enough strength, neurotransmitters will be released at a faster rate than re-uptake can recycle them which will ultimately deplete them until there are no longer readily releasable vesicles and a signal can no longer be transmitted.
causes an exponential decay of the synaptic response amplitudes in the neurons of many neural networks, specifically the caudal pontine reticular nucleus (PnC). Recent research has suggested that only repeated burst stimulation, as opposed to single or paired pulse stimulation, at a very high frequency can result in SF. Some cells like aortic baroreceptor neurons could have devastating effects including the inability to regulate aortic blood pressure if the onset of synaptic fatigue were to affect them. Metabotropic glutamate autoreceptor activation in these neurons may inhibit synaptic transmission by inhibiting calcium influx, decreasing synaptic vesicle exocytosis and modulating the mechanisms governing synaptic vesicle recovery and endocytosis. These glutamate autoreceptors are able to inhibit synaptic fatigue in order to prevent the detrimental physiological consequences that could result from dysfunctional blood pressure regulation in the aorta.
. Because each presynaptic cell can link up to thousands of connections with other neurons, synaptic fatigue and its recovery can cause interactions with other neuronal circuits and can affect the kinetics with other processes of neurons. It is important that the recycling of neurotransmitters take place at an effective and efficient rate in order to prevent synaptic fatigue from negatively affecting signal transmission.
is caused by homosynaptic
depression. Although homosynaptic and heterosynaptic
depression can lead to long-term depression
and/or potentiation
, this particular case is a short-term example of how homosynaptic depression causes synaptic fatigue. Perforant path–granule cells (PP-GC) in the dentate gyrus
of the hippocampus
in adult rats have been shown to experience fatigue at lower frequencies (0.05-0.2Hz). In the developing rat PP-GCs, two types of synaptic plasticity were shown to lead to synaptic fatigue. A low frequency reversible depression of presynaptic vesicle release and a form of nonreversible depression caused by AMPA
silencing. The second form of plasticity disappears with maturation of PP-GCs, although the reversible low frequency depression remains unchanged.
pathology, although the degrees at which it is activated in cells has been studied as result of particular pathologies and diseases. Long-term changes in a neuron or synapse, resulting in a permanent change in a neuron's excitatory properties can cause synaptic fatigue to occur from much more or less activation that could potentially lead to some sort of physiological abnormality.
(AD) are impairment of cognition, aggregation of β-amyloid peptide (Aβ), neurofibrillary degeneration, loss of neurons with accelerated atrophy
of specific brain areas, and decrease of synapse number in surviving neurons. Research indicates both pre- and postsynaptic mechanisms resulting in AD. One specific abnormality includes an increased amount of presynaptic protein APP
. A study was conducted where synaptic fatigue was compared between transgenic mice overexpressing APP/PS1 with their littermates who did not overexpress the protein. The results showed that fatigue was more significantly pronounced in the APP/PS1 mice, which indicates a decrease in the amount of readily releasable pools of vesicles in the presynaptic neuron. Conclusions from this study include synaptic fatigue being primarily a presynaptic phenomenon and not being affected by postsynaptic receptor desensitization
, synaptic fatigue is not a result of Ca2+ ions building up in the terminal, and most importantly that synaptic fatigue is an important player and can be studied when researching the causes and effects of some neurodegenerative
diseases.
patients. The short-term effects are explained by a hypothesis that states that depression is acutely brought on by an immediate decrease in catecholamines in the brain. Antidepressants act immediately to inhibit this decrease and restore normal levels of these neurotransmitters in the brain. Under stressed conditions, vesicle exocytosis
is potentiated and a release of catecholamines causes depression of presynaptic cells because of depleted neurotransmitters. Therapeutic doses of fluoxetine
have been shown to decrease these neuronal fatigue states by inhibiting vesicle release and thereby preventing synaptic fatigue in hippocampal
neurons. These findings show that fluoxetine as well as other antidepressants that act through the same mechanisms as fluoxetine enhance neurorecovery and neurotransmission to reduce the risk of depression.
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
that affects neuronal efficacy and results in the temporary inability to fire and therefore transmit an input signal. It is thought to be a form of negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
in order to physiologically control particular forms of nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
activity. Synaptic fatigue involves the temporary inhibition of neurons
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
due to constant and persistent stimulation, where the fatigue effects are generally dependent upon the type and frequency of stimuli present. The underlying cause of fatigue on the synapse is temporary depletion of synaptic vesicles
Synaptic vesicle
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...
that house neurotransmitters
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the presynaptic cell. The neurotransmitters are released to propagate the signal to the postsynaptic cell. It has also been hypothesized that synaptic fatigue could be a result of postsynaptic receptor desensitization or changes in postsynaptic passive conductance, but recent evidence has suggested that it is primarily a presynaptic phenomenon.
Background
Chemical synapsesChemical synapse
Chemical synapses are specialized junctions through which neurons signal 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...
allow for signal transmission by a presynaptic cell releasing neurotransmitters into the synapse to bind to receptors on a postsynaptic cell. These neurotransmitters are synthesized in the presynaptic cell and housed in vesicles until released. Once neurotransmitters are released into the synaptic cleft and a signal is relayed, re-uptake
Reuptake
Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse....
begins which is the process of transport proteins clearing out the neurotransmitters from the synapse and recycling them in order to allow for a new signal to be propagated. If stimulation is occurring at a high enough frequency and with enough strength, neurotransmitters will be released at a faster rate than re-uptake can recycle them which will ultimately deplete them until there are no longer readily releasable vesicles and a signal can no longer be transmitted.
Functional significance
It has previously been shown that repeated short trains of action potentialsAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
causes an exponential decay of the synaptic response amplitudes in the neurons of many neural networks, specifically the caudal pontine reticular nucleus (PnC). Recent research has suggested that only repeated burst stimulation, as opposed to single or paired pulse stimulation, at a very high frequency can result in SF. Some cells like aortic baroreceptor neurons could have devastating effects including the inability to regulate aortic blood pressure if the onset of synaptic fatigue were to affect them. Metabotropic glutamate autoreceptor activation in these neurons may inhibit synaptic transmission by inhibiting calcium influx, decreasing synaptic vesicle exocytosis and modulating the mechanisms governing synaptic vesicle recovery and endocytosis. These glutamate autoreceptors are able to inhibit synaptic fatigue in order to prevent the detrimental physiological consequences that could result from dysfunctional blood pressure regulation in the aorta.
Synaptic recovery
When synaptic vesicles release neurotransmitters into the synapse that bind with post-synaptic membrane proteins to pass a signal, neurotransmitter re-uptake occurs to recycle neurotransmitters in the presynaptic cell in order to be released again. Neurotransmitter vesicles are recycled through the process of endocytosisEndocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. Because each presynaptic cell can link up to thousands of connections with other neurons, synaptic fatigue and its recovery can cause interactions with other neuronal circuits and can affect the kinetics with other processes of neurons. It is important that the recycling of neurotransmitters take place at an effective and efficient rate in order to prevent synaptic fatigue from negatively affecting signal transmission.
Timing
Maintaining a readily releasable vesicle pool is important in allowing for the constant ability to pass physiological signals between neurons. The timing it takes for neurotransmitter to be released into the synaptic cleft and then be recycled back to the presynaptic cell to be reused is not currently well understood. There are two models currently proposed to attempt to understand this process. One model predicts that the vesicle undergoes complete fusion with the presynaptic cellular membrane once all its contents have been emptied. It then must retrieve vesicular membrane from other sites which could take up to tens of seconds. The second model tries to explain this phenomenon by assuming the vesicles immediately begin to recycle neurotransmitters after release, which takes less than a second to complete endocytosis. One study showed varying times of complete endocytosis ranging from 5.5-38.9 seconds. It also indicated that these times were completely independent of long term or chronic activity.Affected cells
Synaptic fatigue can affect many synapses of many different types of neurons. The existence and observations of synaptic fatigue are accepted universally, although the exact mechanisms underlying the phenomenon are not completely understood. It is generally seen in mature cells at high frequencies of stimuli (>1Hz). One specific example is that the gill withdrawal reflex of the AplysiaAplysia
Aplysia is a genus of medium-sized to extremely large sea slugs, specifically sea hares, which are one clade of large sea slugs, marine gastropod mollusks. The general description of sea hares can be found in the article on the superfamily Aplysioidea....
is caused by homosynaptic
Homosynaptic
Homosynaptic interactions are events that occur at the junctions where neurons meet. Homosynaptic events occur at a single synapse or group of synapses but do not involve interactions between synapses or groups of synapses. This term is often used in relation to long-term depression and long-term...
depression. Although homosynaptic and heterosynaptic
Heterosynaptic
Heterosynaptic phenomena are events that occur at the junctions that form connections between neurons. A heterosynaptic phenomenon is one that involves interactions between separate synapses or groups of synapses. This term is often used in relation to long-term depression and long-term...
depression can lead to long-term depression
Long-term depression
Long-term depression , in neurophysiology, is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress...
and/or potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
, this particular case is a short-term example of how homosynaptic depression causes synaptic fatigue. Perforant path–granule cells (PP-GC) in the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
of the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
in adult rats have been shown to experience fatigue at lower frequencies (0.05-0.2Hz). In the developing rat PP-GCs, two types of synaptic plasticity were shown to lead to synaptic fatigue. A low frequency reversible depression of presynaptic vesicle release and a form of nonreversible depression caused by AMPA
AMPA
AMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate....
silencing. The second form of plasticity disappears with maturation of PP-GCs, although the reversible low frequency depression remains unchanged.
Role in neural plasticity
Synaptic vesicles are thought to be part of three distinct pools: the readily releasable pool (comprises approximately 5% of total vesicles), the recycling pool (about 15%), and the reserve pool (the remaining 80%). The reserve pool seems to only begin to release vesicles in response to intense stimulation. There have been several studies that suggest the reserve vesicles are seldom ever released in response to physiological stimuli which raises questions about their importance. This release in vesicles, regardless of which pool they are released from, is considered a form of short term synaptic plasticity because it is changing the functional characteristics of the presynaptic cell ultimately temporarily altering its firing properties. The difference between this and long-term potentiation is the fact that this phenomenon only occurs for the duration of time it takes to recycle and reuse neurotransmitters as opposed to it occurring over the long-term such as the characteristics underlying long-term potentiation. Further research should be conducted to identify the importance of the reserve pool vesicles in presynaptic cells.Role in CNS pathologies
Synaptic Fatigue has not been shown to directly cause or result in a central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
pathology, although the degrees at which it is activated in cells has been studied as result of particular pathologies and diseases. Long-term changes in a neuron or synapse, resulting in a permanent change in a neuron's excitatory properties can cause synaptic fatigue to occur from much more or less activation that could potentially lead to some sort of physiological abnormality.
Alzheimer's Disease
Hallmarks of Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(AD) are impairment of cognition, aggregation of β-amyloid peptide (Aβ), neurofibrillary degeneration, loss of neurons with accelerated atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
of specific brain areas, and decrease of synapse number in surviving neurons. Research indicates both pre- and postsynaptic mechanisms resulting in AD. One specific abnormality includes an increased amount of presynaptic protein APP
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
. A study was conducted where synaptic fatigue was compared between transgenic mice overexpressing APP/PS1 with their littermates who did not overexpress the protein. The results showed that fatigue was more significantly pronounced in the APP/PS1 mice, which indicates a decrease in the amount of readily releasable pools of vesicles in the presynaptic neuron. Conclusions from this study include synaptic fatigue being primarily a presynaptic phenomenon and not being affected by postsynaptic receptor desensitization
Homologous desensitization
Homologous desensitization occurs when a receptor decreases its response to a signalling molecule when that agonist is in high concentration. It is a process whereby after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade, and thus the biological effect of receptor...
, synaptic fatigue is not a result of Ca2+ ions building up in the terminal, and most importantly that synaptic fatigue is an important player and can be studied when researching the causes and effects of some neurodegenerative
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
diseases.
Depression
Antidepressants have short-term and long-term effects in depressedDepression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
patients. The short-term effects are explained by a hypothesis that states that depression is acutely brought on by an immediate decrease in catecholamines in the brain. Antidepressants act immediately to inhibit this decrease and restore normal levels of these neurotransmitters in the brain. Under stressed conditions, vesicle exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
is potentiated and a release of catecholamines causes depression of presynaptic cells because of depleted neurotransmitters. Therapeutic doses of fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
have been shown to decrease these neuronal fatigue states by inhibiting vesicle release and thereby preventing synaptic fatigue in hippocampal
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
neurons. These findings show that fluoxetine as well as other antidepressants that act through the same mechanisms as fluoxetine enhance neurorecovery and neurotransmission to reduce the risk of depression.