There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science.
A quick but effective summary of Hebbian theory is that "cells that fire together, wire together", together being the key word here which will be explained shortly.
LTP, or long-term potentiation, is the increase of synapse sensitivity due to a prolonged period of activity in both the presynaptic and postsynaptic neuron.
It is called "coincidence" detection in that it only strengthens the synapse if there was sufficient activity in both the presynaptic and postsynaptic cells.
When a glutamatergic synapse releases glutamate it binds to any AMPA and the NMDA receptors present in the postsynaptic membrane.
Sufficient depolarization in the membrane will cause the magnesium cation blockade in the NMDA receptors to vacate, thus allowing calcium influx into the cell.
The rearrangement of AMPA and NMDA receptors has become the central focus of current studies of metaplasticity as it directly determines LTP and LTD thresholds.
[4] There is large amounts of research focused on finding the specific enzymes and intracellular pathways involved in the NMDAR-mediated modulation of membrane AMPA receptors.
Recent biochemical research has shown that a deficiency in the protein tenascin-R (TNR) leads to a metaplastic increase in the threshold for LTP induction.
Prolonged low-frequency stimulation (5 Hz, the method used to induce LTD) can move an active synapse to depressed and then silent.
When new receptor proteins are being expressed and synthesized they must also be transported to the synaptic membrane, and some sort of chemical messaging is required for this.
Their research has shown that activation of cAMP/PKA signaling pathways is required for LTP induction due to its "tagging" nature.
The GluN2B subunit not only is more sensitive to glutamate and takes longer to desensitize, but also allows more calcium entrance into the cell when it opens.
A low GluN2A/GluN2B ratio is generally correlated with a decreased threshold of activation caused by rearing animals in light-deprived environments.
An essential factor in this research is the fact that astrocytes will vary their coverage of neurons based on the physiological processes of the body.
Oxytocin and vasopressin neurons will have more NMDA receptors exposed due to astrocyte activity during lactation than during normal functioning.
With homeostatic mechanisms in place there is now a sort of "gain control" which allows these Hebbian methods to be checked in order to maintain their information processing abilities.
[2] This kind of modulation is important to combat intense lack of neural activity, such as prolonged sensory deprivation (in this study in particular it is light-deprivation affecting visual cortex neurons) or damage caused by stroke.
It has been shown that both the presynaptic and the postsynaptic neuron are involved in the process, changing the vesicle turnover rate and AMPA receptor composition respectively.
[10] Recent research has found that the calcium-dependent enzyme CaMKII, which exists in an alpha and beta isoform, is key in inactivity-dependent modulation.
A low alpha/beta ratio causes an increased threshold for cellular excitation via calcium influx and thus favors LTP.
LTD from the synaptic downscaling of the slow wave activity causes just the right amount of reduction to our neuronal firing patterns.
When studying the effects of sleepiness on fish, it was found that any significant amount of melatonin causes a "dramatic decrease" in learning and memory formation.
[14] This study was performed at night under bright lights, to inhibit the release of natural amounts of melatonin and learning behaviors were conducted.
The authors also gave a drug to the fish to help block the effects of melatonin and then studied their behavioral patterns on memory formation and retrieval.
It was found that in the daytime when melatonin was artificially administered, the fish's ability to learn new material was at its lowest.
[14] As one stays awake for a long time, so much extra potentiation has already happened from the waking day, and trying to force more LTP isn't going to help anything.
The melatonin would work in conjunction with the LTD during slow oscillations during sleep, to keep individuals from potentiating unwanted, or unneeded, information from their day.
During sleep, the slow wave oscillations cause an overall synaptic depression throughout the brain, where only the stronger neuronal pathways are kept from the previous day's LTP.
This inhibition of inhibitory neurotransmission primes proximal excitatory synapses for future LTP induction and is thus metaplastic in nature.