Synaptic scaling

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. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections by decreasing the strength of each synapse by the same factor (multiplicative change), so that the relative synaptic weighting of each synapse is preserved. 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. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections by decreasing the strength of each synapse by the same factor (multiplicative change), so that the relative synaptic weighting of each synapse is preserved. 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. 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. 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: 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. 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.