Non-synaptic plasticity
Encyclopedia
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 (EPSPs) and Inhibitory postsynaptic potentials(IPSPs). 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.
depends on the integration of all the incoming EPSPs and IPSPs arriving at the axon hillock
. If the summation of all exitatory and inhibitory signals depolarize
the cell membrane to the threshold voltage, an action potential is fired. Changing the intrinsic excitability of a neuron will change that neuron's function.
. The increase in spike generation has been correlated with a decrease in the spike threshold
, a response from nonsynaptic plasticity. This response can result from the modulation of certain presynaptic K+ (potassium ion) currents; IA,IK,Ca,and IKs, which work to increase the excitability of the sensory neurons, broaden the action potential, and enhance neurotransmitter
release. These modulations of K+ conductances serve as common mechanisms for regulating excitability and synaptic strength.
of nonsynaptic changes, affecting the change in cellular excitability. Moderate levels of synaptic plasticity produce nonsynaptic changes that will synergistically act with the synaptic mechanisms to strengthen a response. Conversely, more robust levels of synaptic plasticity will produce nonsynaptic responses that will act as a negative feedback mechanism
. The negative feedback mechanisms work to protect against saturation or suppression of the circuit activity as a whole.
changes. This causes the neuron to behave differently when stimulated. The modulation of ion-channels is a response to a change in the stimulation frequencies of a neuron.
Because it is the summation of the action potentials that eventually result in the threshold polarization being crossed, the temporal relationship of different input signals is very important in determining if and when a post-synaptic neuron will fire. Over time, the time it takes an action potential to propagate down the length of a particular axon
can change. In one experiment multielectrode array
s were used to measure the time it took for action potentials to travel from one electrode to another, called latency. The neurons were then stimulated and the value of the latency was recorded over time. The latency values changed over time, suggesting that axonal plasticity influenced the propagation of action potentials.
Shunting is a process in which axon ion-channels open during the passive flow (not requiring an ion pump) of a subthreshold depolarization down the axon. Usually occurring at axonal branch points, the timing of these channels opening as the subthreshold signal arrives in the area causes a hyperpolarization to be introduced to the passively flowing depolarization. Therefore, the cell is able to control which branches of the axon the subthreshold depolarization current flows through, resulting in some branches of the axon being more hyperpolarized than others. These differing membrane potentials cause certain areas of the neuron to be more excitable than others, based on the specific location and occurrence of shunting.
High frequency stimulation of a neuron for a short period of time increases the excitability of the neuron by lowering the amount of voltage
required to fire an action potential.
High frequency stimulation leads to an increase in the intracellular concentration of sodium ions due to the repeated opening of voltage-gated sodium channels
in the axon and terminal. As the frequency of stimuli increases, there is less time between each stimulus for the cell to repolarize
and return to normal resting potential
. Therefore, the resting potential
becomes more depolarized, meaning a smaller depolarizing current is needed to fire an action potential.
However, this modulation is usually very short lived. If the stimulation ceases, the neuron will revert back to its original resting potential as the ion-channels and pumps have ample time to recover from the last stimulus.
High frequency stimulation of a neuron over a long period of time causes two resulting neuronal changes. Initially, the neuron responds as it would during short term stimulation, with an increase in excitability. Continuing the high frequency stimulation after this point results in a drastic, non-reversible change in excitability. When sodium concentrations reach a high enough level in the axon, sodium/calcium pumps reverse their direction of flow, causing calcium to be imported into the cell as sodium is exported out. The increased calcium concentration (and subsequent depolarization of the membrane) inactivates sodium channels and targets them for endocytosis
and lysosomal
hydrolysis
.
This results in a major decrease in axonal sodium channels, which are necessary for action potential
propagation. If the stimulation continues, eventually the neuron will stop transmitting action potentials and will die. Neuronal death due to overstimulation is called excitotoxicity
.
(CNS) neurons integrate signals from many neurons. In the short term, it is very important to have changes in activity of the neuron because this is how information is conveyed in the nervous system. However, for long term sustainability, drift towards exicitability or inexcitability will disturb the circuit's ability to convey information. Long-term potentiation
(LTP) induces a higher firing rate in post synaptic neurons. Without a homeostatic
mechanism, this would result in downstream saturation and all information would be lost. If a neuron could achieve any firing rate, saturation would not be an issue, but firing rates are bounded at zero and a maximal rate of firing. The entire dynamic range (0-maximum) of a neuron's firing rates should be used to encode information. Ideally, the intrinsic properties of a neuron should be arranged to make the most of the dynamic range, acting as a homeostatic mechanism. In vitro studies have found that when the spontaneous activity of neuronal cultures is inhibited, the neurons become hyper excitable and that when an increase in activity is induced for long periods, the firing rates of the culture drop.
pyramidal neurons maintain stability through the regulation of ionic conductances. The regulation of ionic conductances
is achieved through the controlled release of brain-derived neurotrophic factor (BDNF). BDNF has also been found to influence synaptic scaling, suggesting that this neurotrophic factor may be responsible for the coordination of synaptic and nonsynaptic mechanisms in homeostatic plasticity.
s. One way that neurons manipulate the integration properties of the dendrites is by changing the number and properties of voltage gated ion channels. Inducing Long-term potentiation
(LTP) in a particular synapse
, results in an increase in excitability of the dendritic
branches specific to that synapse. Dendritic excitability is important for the propagation and integration of synaptic signals. Dendritic excitability is thought to contribute to E-S potentiation, or an increase in the probability that a given input will result in the firing of an action potential.
It is known that changes in dendritic excitability affect action potential back propagation. Action potentials begin near the axon hillock
and propagate down the length of the axon, but they also propagate backward through the soma
into the dendritic arbor
. Active back propagation is dependent on ion channel
s and changing the densities or properties of these channels can influence the degree to which the signal is attenuated
. Plasticity of back-propagation in the dendrites occurs in less than one minute and lasts longer than 25 minutes. Back propagation is a method of signaling to the synapses that an action potential was fired. This is important for spike-timing-dependent plasticity.
from conditioned stimuli increased the neuronal network response. This depolarization lasted as long as the long-term memory
. Persistent depolarization and behavioral memory
expression occurred more than 24 hours after training, indicating long-term effects. In this experiment, the electrophysiological
expression of the long-term memory trace was a conditioned stimulus induced feeding response. CGCs were significantly more depolarized in the trained organisms than the control group, indicating association with learning and excitability changes. When CGCs were depolarized, they showed an increased response to the conditional stimuli and a stronger fictive feeding response. This demonstrated that the depolarization is enough to produce a significant feeding response to the conditioned stimuli. Additionally, no significant difference was observed in the feeding rates between conditioned organisms and ones that were artificially depolarized, reaffirming that depolarization is sufficient to generate the behavior associated with long-term memory.
Woody et al. showed that classical conditioning
of cat eyeblink reflex
is associated with increased excitability and input in the neurons in sensorimotor cortical areas and in the facial nucleus. It was observed that increasing excitability from classical conditioning continued after the response stopped. This could indicate that increased excitability functions as a mechanism for memory storage.
Experiments have revealed that nonsynaptic changes take place during conditional learning
. In eyelid conditioning
in rabbits, nonsynaptic changes occurred throughout the dorsal hippocampus
. This indicates that although excitability changes alone are not enough to explain memory storage processes, nonsynaptic plasticity might be a storage mechanism for phases of memory limited by time. Nonsynaptic changes influence other types of plasticity involved with memory. For example, a nonsynaptic change like depolarization of the resting membrane potential
resulting from conditional learning could cause synaptic plasticity in future learning.
The ability to learn rules is dependent on nonsynaptic plasticity. One study sought to teach rats to discriminate between various odors, and it took several days to teach them to distinguish between a first pair of odors. However, after learning this, the rat was able to learn to distinguish between different odors much faster. Changes in excitability of the pyramidal neurons in these rats were observed for three days after training. These changes faded eventually, suggesting that the neurons were involved in learning the rules, not in storing memory.
storage systems is very large, making it an attractive mechanism to study. There are approximately 104 synapses per neuron and 1011 neurons in the human brain. Nonsynaptic plasticity is often overlooked simply because its storage capacity is not as high. Regulating the density of ion channels in the axon
and soma
of a neuron
would change the throughput and affect all of the synapses, meaning its storage capacity would be significantly less than that of synaptic plasticity
.
While its storage capacity is too low to make it the sole mechanism for storage, nonsynaptic plasticity could contribute to synaptic storage methods. It has been shown that the modulation of ion channels can be in regions as small as specific dendrites. This specificity makes the storage capacity of nonsynaptic plasticity larger than if it were taken to be whole neuron modulation. Procedural memories
are a good fit for this type of storage system because they do not require the high specificity that declarative memories do. Generalization of motor tasks and conditioned
stimuli could be an efficient way to store this information.
. When one of the vestibular nerves
is damaged, disparity in the firing rates of neurons in the vestibular nuclei
causes unnecessary vestibular reflexes. The symptoms of this damage fade over time. This is likely due to modifications of intrinsic excitability in the neurons of the vestibular nucleus.
activity. Febrile seizures, seizures due to fever, early in life can lead to increased excitability of hippocampal neurons. These neurons become highly sensitized to convulsant agents. It has been shown that seizures early in life can predispose one to more seizures through nonsynaptic mechanisms.
Trauma including stroke
that results in cortical
injury often results in epilepsy
. Increased excitability and NMDA
conductances result in epileptic activity, suggesting that nonsynaptic plasticity may be the mechanism through which epilepsy is induced after trauma.
(VPA) is a treatment for epilepsy
, migraines, and bipolar disorder
that has been linked to many conditions including autism
. An animal model of autism exists in which pregnant rats are given VPA. The offspring have traits similar to those of humans with autism and shortly after birth, these animals exhibit decreased excitability and increased NMDA
currents. These effects are corrected at later stages in life. The changes in intrinsic excitability in these animals helped to offset the effects of increased NMDA currents on network activity, a form of homeostatic plasticity. It is believed that this helps mediate the detrimental effects that the increased NMDA currents would have.
is the ability of a particular part or region of a neuron to change in strength over time. There are two largely recognized categories of plasticity, synaptic and nonsynaptic. Synaptic plasticity
deals directly with the strength of the connection between two neurons, including amount of neurotransmitter
released from the presynaptic neuron
, and the response generated in the postsynaptic neuron
. Nonsynaptic plasticity involves modification of neuronal excitability in the axon
, dendrites, and soma
of an individual neuron, remote from the synapse.
is the ability of a synapse between two neurons to change in strength over time. Synaptic plasticity is caused by changes in use of the synaptic pathway, namely, the frequency of synaptic potentials and the receptors used to relay chemical signals. Synaptic plasticity plays a large role in learning and memory in the brain. Synaptic plasticity can occur through intrinsic mechanisms, in which changes in synapse strength occur because of its own activity, or through extrinsic mechanisms, in which the changes in synapse strength occur via other neural pathways. Short-term inhibitory synaptic plasticity often occurs because of limited neurotransmitter
supply at the synapse, and long term inhibition can occur through decreased receptor expression in the postsynaptic cell
. Short term complementary synaptic plasticity often occurs because of residual or increased ion flow in either the presynaptic or postsynaptic terminal, and long term synaptic plasticity can occur through the increased production of AMPA
and NMDA
glutamate receptors, among others, in the postsynaptic cell.
, the axon
, or the dendrites. Non-synaptic plasticity can have short-term or long-term effects. One way these changes occur is through modification of voltage-gated channels in the dendrites and axon, which changes the interpretation of excitatory or inhibitory potentials propagated to the cell. For example, axonal nonsynaptic plasticity can be observed when an action potential
fails to reach the presynaptic terminal due to low conduction or buildup of ions.
was discovered and researched far before nonsynaptic plasticity, both are essential in the brain, especially to memory
and learning
. In fact, there is much evidence that the two mechanisms both work to achieve the observed effects, but by different mechanisms. A key example of this is in memory formation. Whereas synaptic plasticity uses the modification of presynaptic release mechanisms and postsynaptic receptors to achieve either long-term potentiation or depression, nonsynaptic plasticity has been shown to use continuous somal depolarization
as a method for learned behavior and memory. In addition, nonsynaptic plasticity can add to the effects of synaptic plasticity, as in the case of voltage-gated ion channels. Nonsynaptic plasticity is the mechanism responsible for modifications of these channels in the axon, leading to a change in strength of the neuronal action potential
. However, this action potential or excitability change will invariably affect the strength of synaptic mechanisms, and thus axonal plasticity aids in synaptic plasticity.
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
that involves modification of ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
function in the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
, dendrites, and cell body that results in specific changes in the integration of Excitatory postsynaptic potentials (EPSPs) and Inhibitory postsynaptic potentials(IPSPs). Nonsynaptic plasticity is a modification of the intrinsic excitability
Membrane potential
Membrane potential is the difference in electrical potential between the interior and exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it...
of the neuron. It interacts with synaptic plasticity
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...
, 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
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
itself. Nonsynaptic plasticity affects synaptic integration
Summation
Summation is the operation of adding a sequence of numbers; the result is their sum or total. If numbers are added sequentially from left to right, any intermediate result is a partial sum, prefix sum, or running total of the summation. The numbers to be summed may be integers, rational numbers,...
, subthreshold propagation, spike generation
Population spike
In neuroscience, a population spike is the shift in electrical potential as a consequence of the movement of ions involved in the generation and propagation of action potentials...
, 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
Neuroscience
Neuroscience is the scientific study of the nervous system. Traditionally, neuroscience has been seen as a branch of biology. However, it is currently an interdisciplinary science that collaborates with other fields such as chemistry, computer science, engineering, linguistics, mathematics,...
, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.
Types of nonsynaptic plasticity
Intrinsic excitability of a neuron
The excitability of a neuron at any point depends on the internal and external conditions of the cell at the time of stimulation. Since a neuron typically receives multiple incoming signals at a time, the propagation of an action potentialAction 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...
depends on the integration of all the incoming EPSPs and IPSPs arriving at the axon hillock
Axon hillock
The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. As a result, the axon hillock is the last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many years it was believed...
. If the summation of all exitatory and inhibitory signals depolarize
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
the cell membrane to the threshold voltage, an action potential is fired. Changing the intrinsic excitability of a neuron will change that neuron's function.
Spike generation
Nonsynaptic plasticity has an excitatory effect on the generation of spikesPopulation spike
In neuroscience, a population spike is the shift in electrical potential as a consequence of the movement of ions involved in the generation and propagation of action potentials...
. The increase in spike generation has been correlated with a decrease in the spike threshold
Action 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...
, a response from nonsynaptic plasticity. This response can result from the modulation of certain presynaptic K+ (potassium ion) currents; IA,IK,Ca,and IKs, which work to increase the excitability of the sensory neurons, broaden the action potential, and enhance neurotransmitter
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...
release. These modulations of K+ conductances serve as common mechanisms for regulating excitability and synaptic strength.
Regulation of synaptic plasticity
Nonsynaptic plasticity has been linked with synaptic plasticity, via both synergistic and regulatory mechanisms. The degree of synaptic modification determines the polarityDepolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
of nonsynaptic changes, affecting the change in cellular excitability. Moderate levels of synaptic plasticity produce nonsynaptic changes that will synergistically act with the synaptic mechanisms to strengthen a response. Conversely, more robust levels of synaptic plasticity will produce nonsynaptic responses that will act as a negative feedback mechanism
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 :...
. The negative feedback mechanisms work to protect against saturation or suppression of the circuit activity as a whole.
Axonal modulation
Axonal modulation is a type of plasticity in which the number, activity, or location of ion-channels in the axonAxon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
changes. This causes the neuron to behave differently when stimulated. The modulation of ion-channels is a response to a change in the stimulation frequencies of a neuron.
Propagation Plasticity
Because it is the summation of the action potentials that eventually result in the threshold polarization being crossed, the temporal relationship of different input signals is very important in determining if and when a post-synaptic neuron will fire. Over time, the time it takes an action potential to propagate down the length of a particular axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
can change. In one experiment multielectrode array
Multielectrode array
Multielectrode arrays or microelectrode arrays are devices that contain multiple plates or shanks through which neural signals are obtained or delivered, essentially serving as neural interfaces that connect neurons to electronic circuitry...
s were used to measure the time it took for action potentials to travel from one electrode to another, called latency. The neurons were then stimulated and the value of the latency was recorded over time. The latency values changed over time, suggesting that axonal plasticity influenced the propagation of action potentials.
Shunting
Shunting is a process in which axon ion-channels open during the passive flow (not requiring an ion pump) of a subthreshold depolarization down the axon. Usually occurring at axonal branch points, the timing of these channels opening as the subthreshold signal arrives in the area causes a hyperpolarization to be introduced to the passively flowing depolarization. Therefore, the cell is able to control which branches of the axon the subthreshold depolarization current flows through, resulting in some branches of the axon being more hyperpolarized than others. These differing membrane potentials cause certain areas of the neuron to be more excitable than others, based on the specific location and occurrence of shunting.
High frequency stimulation
- Short term effects:
High frequency stimulation of a neuron for a short period of time increases the excitability of the neuron by lowering the amount of voltage
Voltage
Voltage, otherwise known as electrical potential difference or electric tension is the difference in electric potential between two points — or the difference in electric potential energy per unit charge between two points...
required to fire an action potential.
High frequency stimulation leads to an increase in the intracellular concentration of sodium ions due to the repeated opening of voltage-gated sodium channels
Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells....
in the axon and terminal. As the frequency of stimuli increases, there is less time between each stimulus for the cell to repolarize
Repolarization
In neuroscience, repolarization refers to the change in membrane potential that returns the membrane potential to a negative value after the depolarization phase of an action potential has just previously changed the membrane potential to a positive value. Repolarization results from the movement...
and return to normal resting potential
Resting potential
The relatively static membrane potential of quiescent cells is called the resting membrane potential , as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential....
. Therefore, the resting potential
Resting potential
The relatively static membrane potential of quiescent cells is called the resting membrane potential , as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential....
becomes more depolarized, meaning a smaller depolarizing current is needed to fire an action potential.
However, this modulation is usually very short lived. If the stimulation ceases, the neuron will revert back to its original resting potential as the ion-channels and pumps have ample time to recover from the last stimulus.
- Long term effects:
High frequency stimulation of a neuron over a long period of time causes two resulting neuronal changes. Initially, the neuron responds as it would during short term stimulation, with an increase in excitability. Continuing the high frequency stimulation after this point results in a drastic, non-reversible change in excitability. When sodium concentrations reach a high enough level in the axon, sodium/calcium pumps reverse their direction of flow, causing calcium to be imported into the cell as sodium is exported out. The increased calcium concentration (and subsequent depolarization of the membrane) inactivates sodium channels and targets them for endocytosis
Endocytosis
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...
and lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
.
This results in a major decrease in axonal sodium channels, which are necessary for action potential
Action 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...
propagation. If the stimulation continues, eventually the neuron will stop transmitting action potentials and will die. Neuronal death due to overstimulation is called excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
.
Homeostatic Plasticity
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...
(CNS) neurons integrate signals from many neurons. In the short term, it is very important to have changes in activity of the neuron because this is how information is conveyed in the nervous system. However, for long term sustainability, drift towards exicitability or inexcitability will disturb the circuit's ability to convey information. Long-term 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...
(LTP) induces a higher firing rate in post synaptic neurons. Without a homeostatic
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
mechanism, this would result in downstream saturation and all information would be lost. If a neuron could achieve any firing rate, saturation would not be an issue, but firing rates are bounded at zero and a maximal rate of firing. The entire dynamic range (0-maximum) of a neuron's firing rates should be used to encode information. Ideally, the intrinsic properties of a neuron should be arranged to make the most of the dynamic range, acting as a homeostatic mechanism. In vitro studies have found that when the spontaneous activity of neuronal cultures is inhibited, the neurons become hyper excitable and that when an increase in activity is induced for long periods, the firing rates of the culture drop.
Mechanism
One mechanism for preserving the dynamic range of a neuron is synaptic scaling. This means that the same scaling is done to each synapse, to either strengthen or weaken all of a neuron’s connections. Scaling can be multiplicative (multiplying or dividing the strength of each synapse by a constant number) or additive (adding or subtracting the same value from the synaptic weight). Homeostatic mechanisms go beyond the synapse. Modulation of the intrinsic excitability of a neuron is a way to maintain stability despite changing numbers and strengths of synapses. Cultured corticalCortex
Cortex may refer to:-Sciences:* Cortex , the outer portion of the stem or root of a plant...
pyramidal neurons maintain stability through the regulation of ionic conductances. The regulation of ionic conductances
Action 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...
is achieved through the controlled release of brain-derived neurotrophic factor (BDNF). BDNF has also been found to influence synaptic scaling, suggesting that this neurotrophic factor may be responsible for the coordination of synaptic and nonsynaptic mechanisms in homeostatic plasticity.
Development
In early development spontaneous activity in the brain helps connections form that may aid function in the real world. During development there is frequent remodeling of connections in the brain. This is true in the very young brain as well. The brain prunes its connections early in life, keeping the ones that are helpful and eliminating others. All of these changes in connectivity, cause large fluctuations in neuronal activity. As the brain forms and removes connections, homeostatic mechanisms are important to help maintain stability.Dendritic Excitability
The dendrites are the regions responsible for the integration of the inputs from other neuronNeuron
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...
s. One way that neurons manipulate the integration properties of the dendrites is by changing the number and properties of voltage gated ion channels. Inducing Long-term 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...
(LTP) in a particular synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, results in an increase in excitability of the dendritic
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
branches specific to that synapse. Dendritic excitability is important for the propagation and integration of synaptic signals. Dendritic excitability is thought to contribute to E-S potentiation, or an increase in the probability that a given input will result in the firing of an action potential.
It is known that changes in dendritic excitability affect action potential back propagation. Action potentials begin near the axon hillock
Axon hillock
The axon hillock is a specialized part of the cell body of a neuron that connects to the axon. As a result, the axon hillock is the last site in the soma where membrane potentials propagated from synaptic inputs are summated before being transmitted to the axon. For many years it was believed...
and propagate down the length of the axon, but they also propagate backward through the soma
Soma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
into the dendritic arbor
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
. Active back propagation is dependent on ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s and changing the densities or properties of these channels can influence the degree to which the signal is attenuated
Attenuation
In physics, attenuation is the gradual loss in intensity of any kind of flux through a medium. For instance, sunlight is attenuated by dark glasses, X-rays are attenuated by lead, and light and sound are attenuated by water.In electrical engineering and telecommunications, attenuation affects the...
. Plasticity of back-propagation in the dendrites occurs in less than one minute and lasts longer than 25 minutes. Back propagation is a method of signaling to the synapses that an action potential was fired. This is important for spike-timing-dependent plasticity.
Experimental evidence
The experiment of Kemenes et al. showed that in an extrinsic modulatory neuron, nonsynaptic plasticity influences the expression of long-term associative memory. The relationship between nonsynaptic plasticity and memory was assessed using cerebral giant cells (CGCs). DepolarizationDepolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
from conditioned stimuli increased the neuronal network response. This depolarization lasted as long as the long-term memory
Long-term memory
Long-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...
. Persistent depolarization and behavioral memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
expression occurred more than 24 hours after training, indicating long-term effects. In this experiment, the electrophysiological
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
expression of the long-term memory trace was a conditioned stimulus induced feeding response. CGCs were significantly more depolarized in the trained organisms than the control group, indicating association with learning and excitability changes. When CGCs were depolarized, they showed an increased response to the conditional stimuli and a stronger fictive feeding response. This demonstrated that the depolarization is enough to produce a significant feeding response to the conditioned stimuli. Additionally, no significant difference was observed in the feeding rates between conditioned organisms and ones that were artificially depolarized, reaffirming that depolarization is sufficient to generate the behavior associated with long-term memory.
Nonsynaptic processes and memory storage
Nonsynaptic activity in the cell is usually expressed as changes in neuronal excitability. This occurs through modulation of membrane components, such as resting and voltage-gated channels and ion pumps. Nonsynaptic processes are thought to be involved in memory storage. One possible mechanism of this action involves marking a neuron that has been recently active with changes in excitability. This would help to link temporally separated stimuli. Another potential mechanism comes from a computational model that indicates that nonsynaptic plasticity may prime circuits for modification in learning because excitability changes may regulate the threshold for synaptic plasticity.Learning
Changes in excitability from learning that act as part of the memory trace do so as primers to initiate further changes in the neurons or by a short term storage mechanism for short term memory. Nonsynaptic plasticity can emerge during learning as a result of cellular processes, although the timing, persistence, and the relationship between nonsynaptic plasticity and synaptic output are all poorly understood. Studies have shown that nonsynaptic plasticity plays an indirect but important role in the formation of memories. Learning-induced nonsynaptic plasticity is associated with soma depolarization.Evidence of learning-dependent nonsynaptic plasticity in vertebrates
Woody et al. showed that classical conditioning
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...
of cat eyeblink reflex
Eyeblink conditioning
Eyeblink conditioning is a form of classical conditioning that has been used extensively to study neural structures and mechanisms that underlie learning and memory. The procedure is relatively simple and usually consists of pairing an auditory or visual stimulus with an eyeblink-eliciting...
is associated with increased excitability and input in the neurons in sensorimotor cortical areas and in the facial nucleus. It was observed that increasing excitability from classical conditioning continued after the response stopped. This could indicate that increased excitability functions as a mechanism for memory storage.
Experiments of trace conditioning
Experiments have revealed that nonsynaptic changes take place during conditional learning
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...
. In eyelid conditioning
Eyeblink conditioning
Eyeblink conditioning is a form of classical conditioning that has been used extensively to study neural structures and mechanisms that underlie learning and memory. The procedure is relatively simple and usually consists of pairing an auditory or visual stimulus with an eyeblink-eliciting...
in rabbits, nonsynaptic changes occurred throughout the dorsal 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...
. This indicates that although excitability changes alone are not enough to explain memory storage processes, nonsynaptic plasticity might be a storage mechanism for phases of memory limited by time. Nonsynaptic changes influence other types of plasticity involved with memory. For example, a nonsynaptic change like depolarization of the resting membrane potential
Resting potential
The relatively static membrane potential of quiescent cells is called the resting membrane potential , as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential....
resulting from conditional learning could cause synaptic plasticity in future learning.
Rule Learning and Savings
Savings is the ability to relearn forgotten information much faster than it was learned originally. Nonsynaptic plasticity is a possible mechanism for this savings effect. During training procedures many neurons experience an increase in intrinsic excitability. This increase in excitability persists even after the memory fades.The ability to learn rules is dependent on nonsynaptic plasticity. One study sought to teach rats to discriminate between various odors, and it took several days to teach them to distinguish between a first pair of odors. However, after learning this, the rat was able to learn to distinguish between different odors much faster. Changes in excitability of the pyramidal neurons in these rats were observed for three days after training. These changes faded eventually, suggesting that the neurons were involved in learning the rules, not in storing memory.
Storage Capacity
The storage capacity of synaptic based memorySynaptic 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...
storage systems is very large, making it an attractive mechanism to study. There are approximately 104 synapses per neuron and 1011 neurons in the human brain. Nonsynaptic plasticity is often overlooked simply because its storage capacity is not as high. Regulating the density of ion channels in the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
and soma
Soma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
of a neuron
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...
would change the throughput and affect all of the synapses, meaning its storage capacity would be significantly less than that of synaptic plasticity
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...
.
While its storage capacity is too low to make it the sole mechanism for storage, nonsynaptic plasticity could contribute to synaptic storage methods. It has been shown that the modulation of ion channels can be in regions as small as specific dendrites. This specificity makes the storage capacity of nonsynaptic plasticity larger than if it were taken to be whole neuron modulation. Procedural memories
Procedural memory
Procedural memory is memory for how to do things. Procedural memory guides the processes we perform and most frequently resides below the level of conscious awareness. When needed, procedural memories are automatically retrieved and utilized for the execution of the integrated procedures involved...
are a good fit for this type of storage system because they do not require the high specificity that declarative memories do. Generalization of motor tasks and conditioned
Classical conditioning
Classical conditioning is a form of conditioning that was first demonstrated by Ivan Pavlov...
stimuli could be an efficient way to store this information.
After Damage
Nonsynaptic plasticity, can function to alleviate the effects of brain damageBrain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
. When one of the vestibular nerves
Vestibulocochlear nerve
The vestibulocochlear nerve is the eighth of twelve cranial nerves, and is responsible for transmitting sound and equilibrium information from the inner ear to the brain...
is damaged, disparity in the firing rates of neurons in the vestibular nuclei
Vestibular nuclei
The vestibular nuclei are the cranial nuclei for the vestibular nerve.In Terminologia Anatomica they are grouped in both the pons and medulla.-Subnuclei:There are 4 subnuclei; they are situated at the floor of the fourth ventricle....
causes unnecessary vestibular reflexes. The symptoms of this damage fade over time. This is likely due to modifications of intrinsic excitability in the neurons of the vestibular nucleus.
Seizure Activity
Nonsynaptic plasticity also plays a key role in seizureSeizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
activity. Febrile seizures, seizures due to fever, early in life can lead to increased excitability of hippocampal neurons. These neurons become highly sensitized to convulsant agents. It has been shown that seizures early in life can predispose one to more seizures through nonsynaptic mechanisms.
Trauma including stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
that results in cortical
Cortex
Cortex may refer to:-Sciences:* Cortex , the outer portion of the stem or root of a plant...
injury often results in epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. Increased excitability and NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
conductances result in epileptic activity, suggesting that nonsynaptic plasticity may be the mechanism through which epilepsy is induced after trauma.
Autism
Valproic AcidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
(VPA) is a treatment for epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, migraines, and bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
that has been linked to many conditions including autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
. An animal model of autism exists in which pregnant rats are given VPA. The offspring have traits similar to those of humans with autism and shortly after birth, these animals exhibit decreased excitability and increased NMDA
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
currents. These effects are corrected at later stages in life. The changes in intrinsic excitability in these animals helped to offset the effects of increased NMDA currents on network activity, a form of homeostatic plasticity. It is believed that this helps mediate the detrimental effects that the increased NMDA currents would have.
Nonsynaptic vs synaptic plasticity
NeuroplasticityNeuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
is the ability of a particular part or region of a neuron to change in strength over time. There are two largely recognized categories of plasticity, synaptic and nonsynaptic. Synaptic plasticity
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...
deals directly with the strength of the connection between two neurons, including amount of neurotransmitter
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...
released from the presynaptic neuron
Chemical 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...
, and the response generated in the postsynaptic neuron
Chemical 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...
. Nonsynaptic plasticity involves modification of neuronal excitability in the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
, dendrites, and soma
Soma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
of an individual neuron, remote from the synapse.
Synaptic plasticity
Synaptic plasticitySynaptic 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...
is the ability of a synapse between two neurons to change in strength over time. Synaptic plasticity is caused by changes in use of the synaptic pathway, namely, the frequency of synaptic potentials and the receptors used to relay chemical signals. Synaptic plasticity plays a large role in learning and memory in the brain. Synaptic plasticity can occur through intrinsic mechanisms, in which changes in synapse strength occur because of its own activity, or through extrinsic mechanisms, in which the changes in synapse strength occur via other neural pathways. Short-term inhibitory synaptic plasticity often occurs because of limited neurotransmitter
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...
supply at the synapse, and long term inhibition can occur through decreased receptor expression in the postsynaptic cell
Chemical 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...
. Short term complementary synaptic plasticity often occurs because of residual or increased ion flow in either the presynaptic or postsynaptic terminal, and long term synaptic plasticity can occur through the increased production of AMPA
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
and NMDA
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
glutamate receptors, among others, in the postsynaptic cell.
Nonsynaptic plasticity
In comparison, nonsynaptic plasticity is manifested through changes in the characteristics of nonsynaptic structures such as the somaSoma
Soma , or Haoma , from Proto-Indo-Iranian *sauma-, was a ritual drink of importance among the early Indo-Iranians, and the subsequent Vedic and greater Persian cultures. It is frequently mentioned in the Rigveda, whose Soma Mandala contains 114 hymns, many praising its energizing qualities...
, the axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
, or the dendrites. Non-synaptic plasticity can have short-term or long-term effects. One way these changes occur is through modification of voltage-gated channels in the dendrites and axon, which changes the interpretation of excitatory or inhibitory potentials propagated to the cell. For example, axonal nonsynaptic plasticity can be observed when an action potential
Action 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...
fails to reach the presynaptic terminal due to low conduction or buildup of ions.
Integration in memory and learning
Although synaptic plasticitySynaptic 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...
was discovered and researched far before nonsynaptic plasticity, both are essential in the brain, especially to memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
and learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
. In fact, there is much evidence that the two mechanisms both work to achieve the observed effects, but by different mechanisms. A key example of this is in memory formation. Whereas synaptic plasticity uses the modification of presynaptic release mechanisms and postsynaptic receptors to achieve either long-term potentiation or depression, nonsynaptic plasticity has been shown to use continuous somal depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
as a method for learned behavior and memory. In addition, nonsynaptic plasticity can add to the effects of synaptic plasticity, as in the case of voltage-gated ion channels. Nonsynaptic plasticity is the mechanism responsible for modifications of these channels in the axon, leading to a change in strength of the neuronal action potential
Action 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...
. However, this action potential or excitability change will invariably affect the strength of synaptic mechanisms, and thus axonal plasticity aids in synaptic plasticity.
Current and future research
Additional research is needed to obtain a broader understanding of nonsynaptic plasticity. Topics that should be further explored include:- Local versus global excitability changes in neuronal networks and maintenance of the memory trace
- Specificity of induction of learning-dependent excitability changes
- Manipulation of learning-dependent excitability changes by pharmaceutical products or genetic mutations and their effects on the memory trace
- Similarities between the molecular mechanisms of synaptic and nonsynaptic plasticity
- Comparison of in vivo patterns of nonsynaptic plasticity with in vitro results