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.
Vs. synaptic plasticity
Neuroplasticity 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.
Synaptic plasticity Synaptic plasticity 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, while long-term synaptic plasticity can occur through the increased production of AMPA and NMDA glutamate receptors, among others, in the postsynaptic cell.
Nonsynaptic plasticity In comparison, nonsynaptic plasticity is a less well known and somewhat new and ongoing field of research in neuroscience. It is manifested through changes in the characteristics of nonsynaptic structures such as the soma (biology), the axon, or the dendrites. Nonsynaptic 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.
Synergistic effects
General excitatory effects Nonsynaptic and synaptic plasticity have been shown to work concurrently in a variety of ways to produce stimulating effects in the neuron. This includes spike generation, a product of nonsynaptic regulation of potassium and other presynaptic ion channels, which increase the response of the excitatory postsynaptic potential through neurotransmitter release and augmentation of the action potential. Nonsynaptic dendritic plasticity also adds to the effects of synaptic plasticity through widening of the action potential. As will be discussed further, brain-derived neurotrophic factor (BNDF) is produced by neurons to coordinate nonsynaptic and synaptic plasticity. Nonsynaptic changes in the somal body, axon, or dendrites of the neuron are inextricably linked to synaptic strength.
Integration in memory and learning Although much more is known about the role of synaptic plasticity in memory and learning, both synaptic and nonsynaptic plasticity are essential to memory and learning in the brain. There is much evidence that the two mechanisms both work to achieve the observed effects synergistically. A key example of this is memory formation in the synapse, in which modification of presynaptic release mechanisms and postsynaptic receptors affects either long-term potentiation or depression. Continuous somal depolarization, on the other hand, has been proposed as a method for learned behavior and memory by nonsynaptic plasticity. Nonsynaptic plasticity also augments the effectiveness of synaptic memory formation by regulation 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, invariably affecting the strength of synaptic mechanisms, and thus the depth and length of memory encoding.
Regulation of synaptic plasticity Nonsynaptic plasticity also has the ability to regulate the effects of synaptic plasticity through negative feedback mechanisms. Change in the number and properties of ion channels in the axon or dendrites has the ability to diminish the effects of a hyperstimulated synapse. In the case of extreme overexcitation of these ion channels, backwards flow of ions into the cell will occur, leading to excitotoxicity and cell death by apoptosis or necrosis.
Intrinsic mechanisms Nonsynaptic neuronal areas such as the axon also have inherent qualities that affect the synapse. These essential mechanisms include the delay in depolarization that action potential undergoes while traveling down the axon. This intrinsic quality slows the propagation of action potentials and is due to the movement of depolarizing current down the cytoplasm and the intermittent placement of sodium channels on the Nodes of Ranvier. These mechanisms always exist, but may change depending on the conditions of the cell soma, axon, and dendrites at the time. Therefore, latency, or delay in propagation of action potentials or excitatory postsynaptic potentials, can be variable. Every excitatory postsynaptic potential that is propagated to a postsynaptic cell is first transmitted through the action potential down the axon in the presynaptic cell, and thus nonsynaptic plasticity inherently affects synaptic plasticity.
Types
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 potential depends on the integration of all the incoming excitatory and inhibitory postsynaptic potentials arriving at the axon hillock. If the summation of all excitatory 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.
Spike generation Nonsynaptic plasticity has an excitatory effect on the generation of spikes. 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.
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 polarity 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.
Axonal modulation Axonal modulation is a type of plasticity in which the number, activity, or location of ion channels in the axon 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 results 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 arrays 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 axonal 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 required to fire an action potential. High frequency stimulation leads to an increase in the intracellular concentration of sodium and calcium ions due to the repeated opening of voltage-gated sodium and calcium 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 to its original resting potential as the ion channels and pumps have ample time to recover from the last stimulus.
Long-term effects: