Synaptic scaling

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In neuroscience, synaptic scaling (or homeostatic scaling) is a form of homeostatic plasticity, in which the brain responds to chronically elevated activity in a neural circuit with negative feedback, allowing individual neurons to reduce their overall action potential firing rate. [1] Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections [2] by decreasing the strength of each synapse by the same factor (multiplicative change), so that the relative synaptic weighting of each synapse is preserved. [1]

Contents

Cellular components involved

  1. (Chemical) Synaptic connection: At chemical synapses, pre-synaptic neurons release vesicles containing neurotransmitters into the synaptic cleft. The extracellular neurotransmitters then interact with particular post-synaptic transmembrane protein receptors to allow a fraction of the neurotransmitters into the post-synaptic neuron.
  2. Pre-synaptic vesicles  : Vesicles are the means of chemical-synaptic plasticity. Pre-synaptic neurons relay information (in the form of neurotransmitters) to post-synaptic neurons via vesicles. The neurotransmitters inside vesicles are transported to the synaptic cleft where they interact with neurotransmitter specific post-synaptic protein receptors.
  3. Glutamate: Glutamate is the primary excitatory neurotransmitter within vertebrates and plays a large role in synaptic plasticity. Stimulus to the pre-synaptic neurons triggers glutamate release into the synaptic cleft via pre-synaptic vesicle release. Once in the synaptic cleft, glutamate can bind and activate post-synaptic glutamatergic protein receptors such as NMDA and AMPA receptors.
  4. Post-synaptic AMPA receptor: AMPA Receptors are trans-membrane protein ionotropic receptors that open and close quickly and are responsible for fast excitatory synaptic communication in the central nervous system. AMPA receptors have four subunits that glutamate can bind to. Depending on the AMPA receptor subunit compositions, the receptor can be permeable to cations such as calcium, sodium, or potassium

Interactions

Synaptic scaling is a post-synaptic homeostatic plasticity mechanism that takes place with changes in the quantity of AMPA receptors at a post-synaptic terminal (the tip of the dendrite belonging to the post-synaptic neuron that meets with the tip of an axon belonging to the pre-synaptic neuron) of a neuron. This closed-loop process gives a neuron the ability to have global negative feedback control of synaptic strength of all its synaptic connections by altering the probability of glutamate (the most common excitatory neurotransmitter) making contact with post-synaptic AMPA receptors. Therefore, a neuron's ability to modulate the quantity of post-synaptic AMPA receptors gives it the ability to achieve a set action potential firing rate. [3]

The probability of glutamate making contact with a post-synaptic AMPA receptor is proportional to the concentration of both trans-membrane glutamate and post-synaptic AMPA receptors. When glutamate and post-synaptic AMPA receptors interact, the post-synaptic cell experiences a temporary depolarizing current, known as an EPSP (excitatory postsynaptic potential). Spatial and temporal accumulation of EPSPs at the post-synaptic neuron increases the likelihood of the neuron firing an action potential. Therefore, the concentrations of extra-cellular glutamate (and other cations) and the quantity of post-synaptic AMPA receptors are directly correlated to a neurons' action potential firing rate. Some theories suggest each neuron uses calcium-dependent cellular sensors to detect their own action potential firing rate. [4] These sensors also formulate input for cell-specific homeostatic plasticity regulation systems. In synaptic scaling, neurons use this information to determine a scale factor. Each neuron subsequently uses the scaling factor to globally scale (either up-regulate or down-regulate) the quantity of transmembrane AMPA receptors at all post-synaptic sites.

Some research indicates there are two mechanistically distinct forms of homeostatic plasticity involving trafficking or translation of AMPA receptors at post-synapse of synaptic connections:

  1. Local synthesis of AMPA receptors: Local area AMPA receptor synthesis takes place within a time scale of 4 hours. mRNA translation frequency inside the post-synaptic neuron alters the quantity of local AMPA receptors produced. This mechanism is used to alter the quantity of post synaptic AMPA receptors over short time periods.
  2. Global synaptic scaling: This form of homeostatic plasticity takes place over a time period of days (24–48 hours) [3] and has a more pronounced effect on the overall firing rate of neurons than local AMPA receptor synthesis. Various intra-cellular transport mechanisms help AMPA receptors migrate to the post-synaptic cleft from the entire cell.

Mechanisms

Local area AMPA receptor translation

The earliest phases of AMPA receptor quantity modulation (within a four-hour time period), are dependent on local area (near the synapse) AMPA receptor synthesis, where mRNAs translate for local AMPA receptor transcription. This mechanism is used to increase the number of post synaptic AMPA receptors over a short time period.

Ibata and colleagues studied local AMPA receptor scaling mechanisms by imaging post-synaptic trans-membrane GluR2 subunits using pharmaceutical manipulations over a time period of 4 hours. [5] Fluorescent microscopy was used to visualize GluR2 proteins at synaptic sites of neurons. The study showed local area AMPA receptor translation takes place when post-synaptic firing and NMDA receptors are blocked simultaneously via pharmaceutical manipulations using APV and TTX to block post-synaptic firing. Dr. Turrigiano hypothesized blocking post-synaptic firing would induce up-regulation of AMPA receptors. Changes in existing GluR-2 protein fluorescence were seen in as little as an hour following a TTX bath. The quantity of synaptic sites stayed constant—indicating this short-term AMPA receptor synthesis takes place only on existing synaptic connections.

Intra-cellular electrophysiology recordings were conducted to verify whether increase in quantity of post-synaptic AMPA receptors equated to up-regulation of synaptic connection strength. Intracellular recordings show robust increase in mEPSC amplitude (approximately 130% above control values) following 4–5 hours of TTX treatment. Longer TTX treatments yielded a more noticeable increase in mEPSC amplitude. This form of AMPA receptor trafficking is hypothesized to be directed by local mRNA transcription.

Global

This form of synaptic scaling takes place over a time period of days and has a more pronounced effect on the overall firing rate of neurons than local AMPA receptor trafficking. Various intracellular transport mechanisms help AMPA receptors migrate from the entire neuron to the post-synaptic cleft.

A long-term, concurrent confocal microscopy and electrophysiology investigation conducted on cortical rat in-vitro neural networks (age > 3 weeks in-vitro) growing on Multi Electrode Arrays examined the correlation between network activity levels and changes in the sizes of individual synapses. [6] Specifically, long-term fluorescent microscopy was used to track changes in the quantity (fluorescence) of PSD-95 molecules at individual synapses over timescales of several days. Since PSD-95 molecules anchor post-synaptic AMPA and NMDA receptors, they serve as reliable quantitative markers for post-synaptic transmembrane glutamate receptors. This investigation consisted of two sets of experiments. In the first set, synapse-morphology and spontaneous neural activity were monitored for about 90 hours (i.e. no external stimuli or pharmaceutical manipulations were used to perturb the neuronal networks). During this period, the sizes of individual synapses were observed to fluctuate considerably; yet distributions of synaptic sizes as well as average synaptic size values remained remarkably constant. It was found that ongoing activity acted to constrain synaptic sizes by increasing the tendency of large synapses to shrink and increasing the tendency of small synapses to grow. Thus, activity acted to maintain distributions of synaptic sizes (at the population level) within certain limits. In the second set of experiments the same analysis was performed after the addition of TTX to block all spontaneous activity. This led to a broadening of synaptic size distributions and to increases in average synaptic size values. When individual synapses were followed over time, their sizes were still found to fluctuate significantly, however now, no relationships were found between the extent or direction of size changes and initial synaptic size. In particular, no evidence was found that changes in synaptic size scaled with initial synaptic size. This indicated that the homeostatic growth in AMPA receptor content associated with the suppression of activity is a population phenomenon, that results from the loss of activity-dependent constraints, not from the scaling of AMPA receptor content at individual synapses.

Relationship to homeostatic and Hebbian plasticity

There is evidence that presynaptic and postsynaptic homeostatic plasticity work in unison to regulate firing rate. [7] Postsynaptic activity blockade (by TTX) in culture can increase mEPSC amplitude and mEPSC frequency. [8] Increases in mEPSC frequency indicates the neurons experience an increase in probability of pre-synaptic glutamate neurotransmitter making contact with a post-synaptic AMPA receptor. Further, it's been shown that pre-synaptic vesicles change in size when action potential firing is blocked via (via TTX). [9]

Presynaptic homeostatic plasticity involves: 1) Size and frequency of pre-synaptic neurotransmitter release (for example modulation of mEPSC). 2) Probability of neurotransmitter vesicle releasing after a firing of action potential. Post-synaptic activity blockade (by TTX) in culture can increase mEPSC amplitude and mEPSC frequency (freq. was only changed in cultures older than 18 days). [8] Increase in mEPSC frequency indicates the neurons experience an increase in probability of pre-synaptic glutamate neurotransmitter making contact with a post-synaptic AMPA receptor.

Hebbian plasticity and homeostatic plasticity have a hand-in-glove relationship. [10] Neurons use Hebbian plasticity mechanisms to modify their synaptic connections within the neural circuit based on the correlated input they receive from other neurons. Long-term potentiation (LTP) mechanisms are driven by related pre-synaptic and post-synaptic neuron firings; with the help of homeostatic plasticity, LTPs and LTDs create and maintain the precise synaptic weights in the neural network. Persisting correlated neural activity—without a homeostatic feedback loop—causes LTP mechanisms to continually up regulate synaptic connection strengths. Unspecified strengthening of synaptic weights causes neural activity to become unstable to the point that insignificant stimulatory perturbations can trigger chaotic, synchronous network-wide firing known as bursts. This renders the neural network incapable of computing. [11] Since homeostatic plasticity normalizes the synaptic strengths of all neurons in a network, the overall neural network activity stabilizes.

Related Research Articles

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

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

In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

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<span class="mw-page-title-main">Neurotransmission</span> Impulse transmission between neurons

Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

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<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

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<span class="mw-page-title-main">Synaptic potential</span> Potential difference across the postsynaptic membrane

Synaptic potential refers to the potential difference across the postsynaptic membrane that results from the action of neurotransmitters at a neuronal synapse. In other words, it is the “incoming” signal that a neuron receives. There are two forms of synaptic potential: excitatory and inhibitory. The type of potential produced depends on both the postsynaptic receptor, more specifically the changes in conductance of ion channels in the post synaptic membrane, and the nature of the released neurotransmitter. Excitatory post-synaptic potentials (EPSPs) depolarize the membrane and move the potential closer to the threshold for an action potential to be generated. Inhibitory postsynaptic potentials (IPSPs) hyperpolarize the membrane and move the potential farther away from the threshold, decreasing the likelihood of an action potential occurring. The Excitatory Post Synaptic potential is most likely going to be carried out by the neurotransmitters glutamate and acetylcholine, while the Inhibitory post synaptic potential will most likely be carried out by the neurotransmitters gamma-aminobutyric acid (GABA) and glycine. In order to depolarize a neuron enough to cause an action potential, there must be enough EPSPs to both depolarize the postsynaptic membrane from its resting membrane potential to its threshold and counterbalance the concurrent IPSPs that hyperpolarize the membrane. As an example, consider a neuron with a resting membrane potential of -70 mV (millivolts) and a threshold of -50 mV. It will need to be raised 20 mV in order to pass the threshold and fire an action potential. The neuron will account for all the many incoming excitatory and inhibitory signals via summative neural integration, and if the result is an increase of 20 mV or more, an action potential will occur.

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<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

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.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

<span class="mw-page-title-main">Synaptic fatigue</span> Form of neural negative feedback

Synaptic fatigue, or short-term synaptic depression, is an activity-dependent form of short term synaptic plasticity that results in the temporary inability of neurons to fire and therefore transmit an input signal. It is thought to be a form of negative feedback in order to physiologically control particular forms of nervous system activity.

<span class="mw-page-title-main">Heterosynaptic plasticity</span>

Synaptic plasticity refers to a chemical synapse's ability to undergo changes in strength. Synaptic plasticity is typically input-specific, meaning that the activity in a particular neuron alters the efficacy of a synaptic connection between that neuron and its target. However, in the case of heterosynaptic plasticity, the activity of a particular neuron leads to input unspecific changes in the strength of synaptic connections from other unactivated neurons. A number of distinct forms of heterosynaptic plasticity have been found in a variety of brain regions and organisms. These different forms of heterosynaptic plasticity contribute to a variety of neural processes including associative learning, the development of neural circuits, and homeostasis of synaptic input.

References

  1. 1 2 Siddoway, Benjamin; Hou, Hailog; Xia, Houhui (March 2014). "Molecular mechanisms of homeostatic synaptic downscaling". Neuropharmacology. 78: 38–44. doi:10.1016/j.neuropharm.2013.07.009. PMC   8262101 . PMID   23911745.
  2. ↑ Turrigiano, G. G.; Nelson, S. B. (2000). "Hebb and homeostasis in neuronal plasticity". Current Opinion in Neurobiology. 10 (3): 358–64. doi:10.1016/s0959-4388(00)00091-x. PMID   10851171. S2CID   20462620.
  3. 1 2 Turrigiano, G. G. (2008). "The self-tuning neuron: Synaptic scaling of excitatory synapses". Cell. 135 (3): 422–35. doi:10.1016/j.cell.2008.10.008. PMC   2834419 . PMID   18984155.
  4. ↑ Marder, E; Goaillard, J. M. (2006). "Variability, compensation and homeostasis in neuron and network function". Nature Reviews Neuroscience. 7 (7): 563–74. doi:10.1038/nrn1949. PMID   16791145. S2CID   2870923.
  5. ↑ Ibata, K; Sun, Q; Turrigiano, G. G. (2008). "Rapid synaptic scaling induced by changes in postsynaptic firing". Neuron. 57 (6): 819–26. doi: 10.1016/j.neuron.2008.02.031 . PMID   18367083.
  6. ↑ Minerbi, A; Kahana, R; Goldfeld, L; Kaufman, M; Marom, S; Ziv, N. E. (2009). "Long-term relationships between synaptic tenacity, synaptic remodeling, and network activity". PLOS Biology. 7 (6): e1000136. doi: 10.1371/journal.pbio.1000136 . PMC   2693930 . PMID   19554080.
  7. ↑ Wallace, W; Bear, M. F. (2004). "A morphological correlate of synaptic scaling in visual cortex". Journal of Neuroscience. 24 (31): 6928–38. doi: 10.1523/JNEUROSCI.1110-04.2004 . PMC   6729610 . PMID   15295028.
  8. 1 2 Wierenga, C. J.; Walsh, M. F.; Turrigiano, G. G. (2006). "Temporal regulation of the expression locus of homeostatic plasticity". Journal of Neurophysiology. 96 (4): 2127–33. doi:10.1152/jn.00107.2006. PMID   16760351.
  9. ↑ Turrigiano, G. G.; Leslie, K. R.; Desai, N. S.; Rutherford, L. C.; Nelson, S. B. (1998). "Activity-dependent scaling of quantal amplitude in neocortical neurons". Nature. 391 (6670): 892–6. Bibcode:1998Natur.391..892T. doi:10.1038/36103. PMID   9495341. S2CID   4328177.
  10. ↑ Turrigiano, G. G. (1999). "Homeostatic plasticity in neuronal networks: The more things change, the more they stay the same". Trends in Neurosciences. 22 (5): 221–7. doi:10.1016/s0166-2236(98)01341-1. PMID   10322495. S2CID   13958949.
  11. ↑ Wagenaar, D. A.; Pine, J; Potter, S. M. (2006). "Searching for plasticity in dissociated cortical cultures on multi-electrode arrays". Journal of Negative Results in BioMedicine. 5: 16. doi: 10.1186/1477-5751-5-16 . PMC   1800351 . PMID   17067395.
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