Chronic activation of the innate immune system is now well established as an underlying factor contributing to neurodegeneration—the progressive dysfunction and loss of neurons in the central nervous system leading to cognitive and motor disorders such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and others. Microglia, the primary immune cells of the brain, are critical in the maintenance of brain homeostasis, but lose their functionality during the course of aging and neurodegenerative diseases. While the majority of innate immune responses to disease stressors are mediated by the microglia, perivascular macrophages and peripheral myeloid cell populations can also gain access to the diseased brain and participate in neuroinflammatory signaling. Thus, a better understanding of how immune responses regulate neuronal homeostasis, and of the circumstances leading to dysregulation in pathological conditions, is essential to developing effective therapies and mitigating disease impact.
In neuroscience, synaptic scaling (or homeostatic scaling) is a form of homeostatic plasticity that allows single neurons to regulate their overall action potential firing rate. Like many other physiological systems, neural electrochemical activity is subject to homeostasis. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling works in unison with other homeostatic plasticity mechanisms to normalize all neural synaptic connections.
Cellular components involved
- (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.
- 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.
- 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.
- 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
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 neurons’ 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:
- 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.
- Global synaptic scaling: This form of homeostatic plasticity takes place over a time period of days (24–48 hours) 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.
- Does sleep helps in ensuring homeostatic plasticity?
- Does stress over activates synaptic activities and creates imbalance in brain cell activities?