Plasticity Product is a term coined by Jerry Rudy to refer to mRNA genetic

Genetics

Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

 artifacts and protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 products triggered by transcription factors leading to long-lasting long term potentiation.

Introduction

The term “plasticity product” was coined by Jerry Rudy to refer to mRNA genetic artifacts and protein products triggered by transcription factors, leading long-lasting long term potentiation (L-LTP) and sustained alterations in synaptic strength.

Rudy differentiates between two types of long term potentiation: S-LTP (short-lasting) and L-LTP (long-lasting). In S-LTP the stimulus is strong enough to induce long-term potentiation but too weak to trigger intracellular events necessary to sustain synaptic changes. L-LTP is much less transient than S-LTP and involves the generation of new protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s through translation and transcription.

Induction of L-LTP depends on the transcription of new mRNA and the translation of these new mRNA into proteins. These steps are encompassed by the genomic signaling hypothesis as follows:

1. A stimulus is strong enough to induce L-LTP is delivered.
2. A signaling cascade begins, leading to phosphorylation of transcription factors.
3. mRNA is produced leading to subsequent translation of new proteins to sustain synaptic changes.

Support for the genomic signaling hypothesis comes from studies conducted by Nguyen et al. demonstrating the inability to induce L-LTP following transcription inhibition immediately following the inducing stimulus but not if transcription is blocked later. The temporal effects of this inhibition suggests that L-LTP is dependent on newly synthesized “plasticity products.”

cAMP-responsive element-binding (CREB) protein, a transcription factor, is also implicated in changes in synaptic plasticity. Inhibition of CREB translation likewise inhibited synaptic changes. CREB is activated in its phosphorylated form, acting as a molecular switch for production of plasticity products.

Two Waves of Protein Synthesis

There are two waves of protein synthesis following LTP induction. The first involves local transcription and translation of mRNA and the second involves the genomic signaling cascade.

Transcription and Local Translation of mRNAs

There is fast-acting, local translation of proteins in the dendritic region near the spines when an inducing high-frequency stimulus is applied, indicating that some plasticity-relevant mRNAs are already present and ready to be translated. To facilitate translation outside of the soma, since synapses depend on some proteins to be synthesized on site, translation machinery such as ribosomal

Ribosome

A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

 assemblies and endoplasmic reticulum

Endoplasmic reticulum

The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 are present in dendrites (specifically in the spine neck and shaft). Local protein synthesis at the dendrites is a mechanism permitting rapid synaptic changes in response to neural activity. However, since the mRNAs existed in the dendrites prior to plasticity-inducing stimulation, they do not count as plasticity products.

Genomic Signaling Cascade

A synapse-to-nucleus or soma-to-nucleus signaling cascade induced by synaptic activity leads to the transcription of new plasticity products in the soma of the cell. Mechanistically, signaling molecules phosphorylate cAMP-responsive element binding protein (CREB), which is a transcription factor and molecular memory switch that initiates production of mRNAs in the cell nucleus. These plasticity products must then travel back to activated synapses, meaning that this wave of plasticity product synthesis is slower.

Examples of Plasticity Products

A plasticity product must fit these criteria:

a) Plasticity products are proteins that are important for the maintenance of long-lasting LTP.

b) Plasticity products result from any cell-signaling cascade that is triggered by strong HFS.

PKM ζ

PKM ζ are protein consequences of LTP stimuli and are crucial components of the short-term LTP mechanism. Recent research concludes that the protein kinase PKMζ is a “core molecule” in maintaining late-LTP. Tetanic stimulation leads to an increase in PKMζ expression, and since PKMζ was established as necessary for maintaining late-LTP. When L-LTP is induced, synthesis of PKMζ from its brain-specific mRNA increases, and this constitutively active kinase maintains LTP in tagged synapses by upregulating AMPA receptor trafficking pathways.

Some experimental results implicating PKM ζ as a plasticity product are as follows:

• Ling et.al. found that PKM ζ is necessary and sufficient for LTP maintenance. When they added an inhibitory form of PKM ζ, LTP was blocked. LTP was also blocked when they added PKM ζ inhibitors.

• Yao et. al. also show that pKM ζ is functionally critical for the maintenance of long-lasting LTP, specifically through its mediation of NSF/GluR2-dependent AMPA receptor trafficking. This conclusion was draw from experiments involving blocking NSF/ GluR2 interactions by adding a myristoylated version of pep2m (a peptide that mimics the NSF - binding site in GluR2). This blockage prevented the expression of LTP persistence at 1 hour after high frequency stimulation (tetanization). Hernandez et. al. found that LTP increases de novo synthesis of PKM ζ. They induced LTP in the CA1 region of hippocampal slices by 2 100Hz 1s trains, 20 s apart. Then they homogenized the slices, and immunoprecipitated PKM ζ with antiserum. Label depicted the new synthesis, of which there was a large increase.

CaMKII

CAMKII (Calcium-calmodulin-dependent protein kinase II) is a protein kinase that must be activated by calmodulin in order to phosphorylate other proteins in the cell. It is important in modifying the postsynaptic response to glutamate (by modifying the conformation of AMPA receptors to allow a larger influx of sodium

Sodium

Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 ion

Ion

An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...

s), and contributes to strengthening synapses. The production of the CAMKII enzyme is upregulated with plasticity-inducing stimuli.

Some experimental results implicating PKM ζ as a plasticity product are as follows:

• Giece et. al. discovered that the calcium-calmodulin-dependent kinase II is required for hippocampal long-term potentiation. When they inhibited CaMKII, LTP was prevented. Also, in genetically altered mice with a CaMKII form that cannot stay active, LTP was greatly reduced.

• However, CaMKII is not synthesized, it is modified, making it a questionable candidate under the above criteria. Researchers Blitzer et. al. show that high frequency stimulation induced cAMP dependent increase in CaMKII phosphorylation and calcium-independent CaMKII activity. CA1 homogenates were probed with an antibody specific for Thr286 – phosphorylated CaMKII and an antibody detecting total CaMKII. They observed a 22% increase in CaMKII activity after LTP-inducing HFS.