Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan.
Frey, a researcher at the Leibniz Institute for Neurobiology (later at the Medical College of Georgia and the Lund University), and Morris, a researcher at the University of Edinburgh,[2] laid the groundwork for the synaptic tagging hypothesis, stating: "We propose that LTP initiates the creation of a short-lasting protein-synthesis-independent 'synaptic tag' at the potentiated synapse which sequesters the relevant protein(s) to establish late LTP.
The experiment performed by Frey and Morris involved the stimulation of two different sets of Schaffer collateral fibers that synapsed on same population of CA1 cells.
When they blocked protein synthesis prior to the delivery of strong S2 stimulation, the conversion to L-LTP was prevented, showing importance of translating the mRNAs produced by the genomic cascade.
[3] This means that mRNAs are not a product of genomic cascade initiated by strong stimulus, but rather, is delivered as a result of continual basal transcription.
Synaptic tagging/ tag-and-capture theory potentially addresses the significant problem of explaining how mRNA, proteins, and other molecules may be specifically trafficked to certain dendritic spines during late phase LTP.
The alternate splicing mechanisms allow cells to produce a diverse set of proteins from a single gene within the genome.
Recent developments in next-generation sequencing have allowed for greater understanding of the diversity eukaryotic cells achieve through splice variants.
[12] Researchers[13] provided evidence of local synthesis, by examining the distribution of Arc mRNA after selective stimulation of certain synapses of a hippocampal cell.
These mRNA transcripts are translated in a cap-dependent manner, meaning they use a "cap" anchoring point to facilitate ribosome attachment to the 5' untranslated region.
[19] One model suggests that the tag allows for local protein synthesis at the specified synapse that then leads to modifications in synaptic strength.
For example, the removal of AMPA receptors due to low-frequency stimulation leading to LTD is stabilized by a new protein product that would be inactive at synapses where internalization had not occurred.
Finally, another model proposes that the required molecular products get directed into the appropriate dendritic branches and then find the specific synapses under efficacy modification, by following Ca++ microconcentration gradients through voltage-gated Ca++ channels.
[20] While the concept of the synaptic tagging hypothesis mainly resulted from experiments applying stimulation to synapses, a similar model can be established considering the process of learning in a broader - behavioral - sense.
When the two behavioral events were coupled within a certain time frame, the weak training was sufficient to elicit task-related changes in long-term memory.