Synaptic scaling

Introduction

In neuroscience, Synaptic Scaling is a form of Homeostatic Plasticity that allows neurons to regulate their overall excitability relative to network wide activity. Like many other physiological systems, neural electrochemical activity is subjected to homeostasis—specifically the overall firing rate of neurons in the network. Synaptic scaling is the best understood form of homeostatic plasticity, and takes place with changes in the quantity of AMPA receptors at the post-synaptic (the tip of the dendrite that meets with the tip of an axon of another cell). Quantity of AMPA receptors are modified (up-regulated or down-regulated) in a proportional manner to achieve a set firing rate. Current research indicates there are two mechanistically distinct forms of homeostatic plasticity involving trafficking of of AMPA receptors: 1) Local area AMPA receptor trafficking: The earliest phases of synaptic scaling (within a four hour time period), are dependent on local area synaptic scaling where of mRNA translate for local AMPA receptor translation . This mechanism is used to increase the number of post synaptic AMPA receptors over a short time period. 2) Global Synaptic Scaling: 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 synaptic scaling. Various intra-cellular transport mechanisms migrate AMPA receptors to the post-synaptic cleft from the entire cell.

Relationship to Homeostatic Plasticity, Hebbian Plasticity, and Network Stability

Synaptic Scaling was first observed by Dr. Turrigiano at 1998 where she demonstrated changes to the over-all network activity via application of TTX (TTX—Tetrodotoxin—binds to voltage-gated NA+ channels, and prevents firing of action potentials at the post-synapse of the cell) change the size of pre-synaptic vesicle release and post-synaptic AMPA receptor trafficking quantity using in-vitro neural networks grown on in-vitro Multi-Electrode Arrays. A different form of neural firing homeostasis takes a pre-synaptic homeostatic plasticity form. Pre-synaptic homeostatic plasticity involves: 1) Quantity of Pre-synaptic neurotransmitter release sites (for example modulation of mini Excitatory Post Synaptic Current). 2) Probability of neurotransmitter vesicle releasing after a firing of action potential. Hebbian Plasticity and Homeostatic Plasticity have a hand-in-glove relationship as explained by Dr. Gina Turrigiano (who has conducted an extensive number of Homeostatic Plasticity experiments). Neurons use Hebbian Plasticity mechanisms to modify their own synaptic connections within the neural circuit based on the input they receive from other cells. Long-Term Potentiation & Long-Term Depression (LTP/LTD) mechanisms are driven by co-related pre-synaptic and post-synaptic neuron firings. LTPs and LTDs create and maintain the precise synaptic weights in the neural network. Homeostatic Plasticity normalizes all the synaptic strengths of the network, thereby stabilizing the overall neural network activity. Without Homeostatic Plasticity, the cell loses the ability to allocate its resources properly, and deviates from the action potential firing set-point. Correlated neural activity causes LTP mechanisms to continually up regulate synaptic connection strengths. Over time, the neurons lose specificity of firing, which renders the neural network incapable of computing for periods of time known as bursting. In addition to Homeostatic Plasticity, AMPA receptor trafficking is modulated by a number of different cellular mechanisms. [Newpher and Ehlers, 2008] has specifically looked at consequential effects of LTP and LTD to AMPA receptor trafficking.

Cellular components involved in Synaptic Scaling Mechanism

Synaptic Scaling involves modulating the quantity of post-synaptic transmembrane AMPA receptors. Modulation of post-synaptic AMPA receptor gives neurons the ability to have global negative feedback control of synaptic strength . Current evidence supports cells having control over how homeostatic plasticity modulates their firing. Neurons can monitor their own firing rates with the help of calcium-dependent cellular sensors. These sensors then provide the input for the homeostatic regulation systems. Synaptic scale takes place globally on a time scale of 24-48 hours. The Synaptic Scaling phenomenon takes place at the post-synaptic cleft of a synaptic connection. Trans-membrane AMPA receptors at this site are either up-regulated or down-regulated in quantity to modulate the excitability of the post-synaptic neuron. AMPA Receptors are trans-membrane ionotropic protein receptors that open and close quickly and are responsible for fast excitatory synaptic communication. AMPA receptor is permeable to Ca2+, Sodium, Potassium, other cations, and glutamate. The transmembrane Glutamate concentrations (and other cation concentrations) are modulated by the concentration of AMPA receptors at the post-synaptic site and accounts for the cells’ long-term excitability known as intrinsic excitability . Glutamate is an excitatory neurotransmitter that is released from pre-synaptic vesicles from the post-synapse into the synaptic cleft. The probability of the glutamate of making contact with the post-synaptic AMPA receptor is proportional to the quantity of both transmembrane glutamate and post-synaptic AMPA receptors.

Synaptic Scaling Mechanisms

Current research indicates there are two mechanistically distinct forms of homeostatic plasticity involving trafficking of AMPA receptors.

Local area AMPA receptor trafficking

The earliest phases of synaptic scaling (within a four hour time period), are dependent on local area synaptic scaling 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. These local homeostatic changes take place when post-synaptic firing and NMDA receptors are blocked simultaneously via pharmaceutical manipulations. looked at local AMPA receptor scaling mechanisms by imaging post-synaptic transmembrane GluR2 subunits over a time period of 4 hours. Changes in GluR-2 puncta fluorescence were seen 4 hours following a TTX bath, indicating an increase of AMPA receptor concentrate at the post-synapse sites. This form of AMPA receptor trafficking is hypothesized to be directed by local mRNA transcription.

Global Synaptic Scaling

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 synaptic scaling. Various intra-cellular transport mechanisms migrate AMPA receptors to the post-synaptic cleft from the entire cell. This longer form of synaptic scaling doesn’t require NMDA receptor blocking. A long-term concurrent imaging and electrophysiology investigation on cortical rat in-vitro neural networks (age > 3 weeks in-vitro) on MEAs conducted by showed the correlation between changes in extra-cellular electrical activity and morphological AMPA receptor. The long-term fluorescent microscopy (confocal microscope) tracked changes in quantity, density, and fluorescence of PSD-95 molecules over a time scale of 90 hours. Since PSD-95 molecules anchor to post-synaptic AMPA and NMDA receptors, they serve as a reliable marker for post-synaptic glutamate receptors. Two sets of experiments were conducted; the first experiment monitored only spontaneous morphological and electrochemical behavior. During this time the number of PSD-95 puncta increased almost linearly with time. The average flourescence per puncta however remained constant throughout the 90 hours. The second experiment involved doing the same analysis, but with the addition of TTX. During this time the quantity of PSD-95 molecules stayed constant, however, the fluorescence of the PSD-95 molecules increased. This data indicates in-vitro neural networks (of at least 3 weeks of age), prefer increasing the concentration of AMPA receptors at post-synaptic sites rather than forming new synaptic sites. The previous statement is also supported by data from which looked at homeostatic activity at different developmental periods for in-vitro networks. In younger cultures (<3 weeks in-vitro), chronic blockade of activity (via pharmaceutical application of TTX) has no lucid effect on pre-synaptic homeostatic plasticity. Whereas in older cultures (>3 weeks in-vitro), post-synaptic activity deprivation increases number of post-synaptic receptor accumulation, number of synaptic contacts, and probability of vesicle release from the pre-synaptic terminal. looked at long-term remodeling of PSD molecules over time with under the influence of various pharmaceutical manipulations. Imaging data (images taken in 30 minutes to one hour intervals over 10-20 hours) from this investigation revealed single PSD-95 molecules were stable for up to ten hours. Both formation of new PSD-95 clusters and elimination of existing PSD-95 clusters took place over a time scale of hours.  

References

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