Synaptic tagging
Synaptic tagging, or the synaptic tagging hypothesis, was first proposed in 1997 by Julietta U. Frey (her publishing name was Uwe Frey or J. U. Frey before the year 2000 (https://scholar.google.com/citations?user=sghJBzMAAAAJ&hl=en&citsig=AD-1fHaN4xLB44tNjIiILbQWZcfn)) and Richard G. Morris; it seeks to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. 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.[1]
Further investigations have suggested that plasticity-related products include
History
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. In support of this idea, we now show that weak tetanic stimulation, which ordinarily leads only to early LTP, or repeated tetanization in the presence of protein-synthesis inhibitors, each results in protein-synthesis-dependent late LTP, provided repeated tetanization has already been applied at another input to the same population of neurons. The synaptic tag decays in less than three hours. These findings indicate that the persistence of LTP depends not only on local events during its induction, but also on the prior activity of the neuron."[2]
L-LTP inducing
The experiment performed by Frey and Morris involved the stimulation of two different sets of
Subsequent research has identified an additional property of synaptic tagging that involves associations between late LTP and LTD. This phenomenon was first identified by Sajikumar and Frey in 2004 and is now referred to as "cross-tagging".
Blitzer and his research team proposed a modification to the theory in 2005, stating that the proteins captured by the synaptic tag are actually local proteins that are translated from mRNAs located in the dendrites.
mRNA trafficking to the dendritic spine and cytoskeleton
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. It has long been known that the late phase of LTP depends on protein synthesis within the particular dendritic spine, as proven by injecting
A cell's identity and the identities of
Transcribed mRNA must reach the intended dendritic spine for the spine to express L-LTP. Neurons may transport mRNA to specific dendritic spines in a package along with a transport ribonucleoprotein (RNP) complex; the transport RNP complex is a subtype of an RNA granule. Granules containing two proteins of known importance to synaptic plasticity, CaMKII (Calmodulin-dependent Kinase II) and the immediate early gene Arc, have been identified to associate with a type of the motor protein kinesin, KIF5.[9] Furthermore, there is evidence that polyadenylated mRNA associates with microtubules in mammalian neurons, at least in vitro.[10] Since mRNA transcripts undergo polyadenylation prior to export from the nucleus, this suggests that the mRNA essential for late-phase LTP may travel along the microtubules within the dendritic shaft prior to reaching the dendritic spine.
Once the RNA/RNP complex arrives via motor protein to an area within the vicinity of the specific dendritic spine, it must somehow get “captured” by a process within the dendritic spine. This process likely involves the synaptic tag created by synaptic stimulation of sufficient strength. Synaptic tagging may result in capture of the RNA/RNP complex via any number of possible mechanisms such as:
- The synaptic tag triggers transient microtubule entry to within the dendritic spine. Recent research has shown that microtubules can transiently enter dendritic spines in an activity-dependent manner. [[11]]
- The synaptic tag triggers the dissociation of the cargo from motor protein and somehow guides it to dynamically formed microfilaments
Local protein synthesis
Since the 1980s, it has become more and more clear that the
Researchers[13] provided evidence of local synthesis, by examining the distribution of Arc mRNA after selective stimulation of certain synapses of a hippocampal cell. They found that Arc mRNA was localized at the activated synapses, and Arc protein appeared there simultaneously. This suggests that the mRNA was translated locally.
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. Eukaryotic initiation factor 4 group (eIF4) members recruit ribosomal subunits to the mRNA terminus, and assembly of the eIF4F initiation complex is a target of translational control: phosphorylation of eIF4F exposes the cap for rapid reloading, quickening the rate-limiting step of translation. It is suggested that eIF4F complex formation is regulated during LTP to increase local translation.[12] In addition, excessive eIF4F complex destabilizes LTP.
Researchers have identified sequences within the mRNA that determine its final destination - called localization elements (LEs), zipcodes, and targeting elements (TEs). These are recognized by RNA binding proteins, of which some potential candidates are MARTA and ZBP1.[14][15] They recognize the TEs, and this interaction results in formation of ribonucleotide protein (RNP) complexes, which travel along cytoskeleton filaments to the spine with the help of motor proteins. Dendritic TEs have been identified in the untranslated region of several mRNAs, like MAP2 and alphaCaMKII.[16][17]
Possible tag models
Synaptic tagging is likely to involve the acquisition of molecular maintenance mechanisms by a synapse that would then allow for the conservation of synaptic changes.
Behavioral tagging
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.[21] Fabricio Ballarini and colleagues developed this behavioral tagging model by testing spatial object recognition, contextual conditioning, and conditioned taste aversion in rats with weak training. The applied training normally only results in alterations of short-term memory. However, they paired this weak training with a separate, arbitrary behavioral event that is assumed to induce protein synthesis. 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. The researchers believed that the weak training lead to a "learning tag". During the subsequent task, the cleavage of proteins resulted in the formation of long-term memory for this tag. The behavioral tagging model corresponds to the synaptic tagging model. A weak stimulation establishes E-LTP that may serve as the tag used in converting the weak potentiation to the stronger, more persistent L-LTP, once the high-intensity stimulation is applied.
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