Nonsynaptic plasticity

Brain connectivity network

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 EPSPs and IPSPs, thus modifying the intrinsic excitability of the neuron. It interacts with synaptic plasticity, however it is considered separate from synaptic plasticity itself. This process is visible in neurons that are actively involved in learning. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the neuronal level. These individual neuronal alterations can result in changes in higher brain function, especially concerning 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.

Types of nonsynaptic plasticity

Forest of synthetic pyramidal dendrites grown using Cajal's laws of neuronal branching

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 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.

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. This is the main form of nonsynaptic plasticity.

Shunting

Shunting is a process in which axonal ion-channels open during the passive flow of a subthreshold depolarization down the axon. Usually ocurring at axonal branch points ^[1] , 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 that others. These differing membrane potentials cause certain areas of the neuron to be more excitable than others, based on the specific location and ocurrence 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 threshold voltage required to fire an action potential.^[2] 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.

• 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 and lysosomal hydrolysis.^[3] 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.

Effects on brain cell 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,^[4] a response from nonsynaptic plasticity. This response can result from the modulation of certain presynaptic K⁺ currents; I_A,I_K,Ca,and I_Ks, 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.^[5]

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.^[5]

Higher brain function involved with nonsynaptic plasticity

Long-term associative memory

Experimental evidence

The experiment of Kemenes et al^[6] 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). Depolarization from conditioned stimuli increased the neuronal network response and occurred postcondtionally. This depolarization lasted as long as the long-term memory. Persistent depolarization and behavioral memory expression occurred more than 24 hours after posttraining, indication long-term effects. In this experiment, the electrophysiological expression of the long-term memory trace was a conditioned stimulus induced fictive 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 fictive feeding response to the conditioned stimuli. Therefore, the depolarization as a result of learning makes a large impact to long-term memory by the activation of the conditioned behavior by the conditioned stimuli. Additionally, no significant difference was observed in the fictive 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.^[6]

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.^[5]

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 in during learning as a result of cellular processes, although the timing and persistence is not well understood, nor is the relationship between nonsynaptic plasticity and synaptic output. 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.^[5]

Classical conditioning

Evidence of learning-dependent nonsynaptic plasticity in vertebrates

Woody et al^[7] showed that classical conditioning of cat eyeblink reflex is associated with increased excitability and input in the neurons in sensorymotor cortical areas and in 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. This was supported by the observation that retraining after suppression of conditioned response produced a much faster rate of learning.^[5]

Experiments of trace conditioning

Experiments have revealed 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 additional conditional learning.^[5]

Nonsynaptic 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, dendritic, and somatic areas of an individual neuron, remote from the synapse.

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 , and long term synaptic plasticity can occur through the increased production of AMPA and NMDA glutamate receptors, among others, in the postsynaptic cell. ^[8]

In comparison, nonsynaptic plasticity is manifested through changes in the characteristics of nonsynaptic structures such as the soma, the axon, or the dendrites. Non-synaptic 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 a potential fails to reach the presynaptic terminal due to low conduction or buildup of ions. ^[6]

Although synaptic plasticity 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. ^{[5] [9]}

Current and future research

Additional research is needed to obtain a broader understanding of nonsynaptic plasticity. Topics that should be further explored include^[5]:

• 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

See also

1. Synaptic plasticity
2. Neuroplasticity

References

1. ^ "Synaptic and non-synaptic plasticity between individual pyramidal cells in the rat hippocampus in vitro". J Physiology: 307–309. 1996. 
2. ^ "Beyond parallel fiber LTD: the diversity of synaptic and non- synaptic plasticity in the cerebellum". Nature Neuroscience 4: 472. May 2001. 
3. ^ "Activity-Dependent Axonal Plasticity: The Effects of Electrical Stimulation on Compound Action Potentials Recorded from the Mouse Nervous System In Vitro". The Open Neuroscience Journal 3: 10. January 2009. 
4. ^ Hansel, Christian; Linden, David J.; D'Angelo, Egidio (2001). "Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum". Nature Neuroscience 4.5: 469–475. doi:10.1038/87419. PMID 11319554. 
5. ^ ^{a b c d e f g h} Mozzachiodi, Riccardo; Byrne, John H. (2009). "More than synaptic plasticity: role of nonsynaptic plasticity in learning memory". Trends in Neuroscience 33.1: 17–26. doi:10.1016/j.tins.2009.10.001. PMID 19889466. 
6. ^ ^{a b c} "Kemenes", Ildiko; Straub (2006). "Role of Delayed Nonsynaptic Neuronal Plasticity in Long-Term Associative Memory". Current Biology 16: 1269–1279. doi:10.1016. 
7. ^ Woody, Charles D; Black-Cleworth, Patricia (1973). "Differences in excitability of cortical neurons as a function of motor projection in conditioned cats.". Journal of neurophysiology 36.6 pages= 1104-1116. PMID 4761722. 
8. ^ Byrne, John H. (1997). "Synaptic Plasticity". Neuroscience Online. The UT Medical School at Houston. http://nba.uth.tmc.edu/neuroscience/s1/chapter07.html. Retrieved October 28, 2011. 
9. ^ Debanne, Dominique (1999). "Gating of action potential propagation by an axonal A-like potassium conductance in the hippocampus: A new type of non-synaptic plasticity". Journal of Physiology: Paris. Éditions scientifiques et médicales Elsevier SAS. http://www.sciencedirect.com/science/article/pii/S0928425700800571#sec1.1. Retrieved October 29, 2011.