To rehash the last segment, axonal action potentials of a sufficient frequency (as in number of depolarizations in a given time interval) trigger plastic effects on the target dendrite in addition to the usual depolarizations associated with nerve conduction. Glutamate released by the axon acts across the synaptic cleft to activate ionotropic receptors (AMPA) in the dendrite cell membrane that cause Sodium ions (Na+) to enter the cell and alter its baseline polarity which may trigger an action potential in the target cell. In addition, the repetitive stimulation prevents the dendrite’s potential from returning to baseline before the next stimulation, resulting in a stacking of charges until a critical threshold is exceeded. Once this threshold is exceeded, changes in the dendrite membrane and glutamate binding to NMDA receptors flushes Magnesium ions (Mg++) out of the receptors allowing Calcium ions (Ca++) to enter the cell. The Calcium activates PKC and Calmodulin kinase (CaMKII) to phosphorylate the AMPA receptors making them more efficient at sodium transport. This lowers the threshold of the cell to future stimulation. Additional AMPA receptors already bound to the dendrite’s cell membrane are recruited into the synaptic cleft, completing the early (independent of protein synthesis) phase of Long Term Potentiation (e-LTP). The major elements of e-LTP are displayed in the first Plinygraph.
This bit covers the late phase of Long Term Potentiation. (Note that not every intermediary in the process is presented nor are all the alternate converging pathways described.) Metabotrophic (second messenger) receptors were briefly mentioned in the last installment but their most significant effects bear on late phase changes in LTP.
Glutamate reversibly binds with the metabotrophic complex (the red bits) which ultimately activate Adenyl cyclase (AC). AC converts ATP from mitochondria into the cytoplasmic second messenger Cyclic AMP (cAMP).
cAMP in combination with a Protein Kinase (PKA) transmits this message to the nucleus of the stimulated neuron. This is but one of a number of cascades available to the cell, including Calmodulin Kinase, growth factors, other neurotransmitters and even cytokines from stress events, that converge within the nucleus to phosphorylate cAMP Response Element-Binding proteins (CREB).
Phosphorylated CREB binds to specific DNA segments in the promotor regions of genes, which can be transcribed into mRNA strands relevant to the translation of the peptide subunits of additional receptors like NMDA. These promotor regions where CREB binds are called cAMP Response Elements (CRE). Bound CREB, in combination with several other proteins, unfolds a segment of DNA and allows RNA Polymerase II to transcribe the relevant mRNA strands.
From the nucleus the mRNA is transported to the endoplasmic reticulum (ER) where protein synthesis generally takes place. ER is one of a number of amazing organelles located within eukaryotic cells. It can be argued that the leap from prokaryote to eukaryote was a far larger change in complexity than the evolution of mammals such as ourselves from single-celled eukaryotes. All of our cells are specialized variations on the basic plan of a eukaryote.
Within the ER, transcribed mRNA copies are translated into new receptor proteins through the interactions of Ribosomes, mRNA, and tRNA-bound amino acids. Technically, the subunit peptides of the proteins get produced in the ER and then are assembled in their final form in the Golgi Apparatus (left off of the diagrams which are complex enough already). There is some controversy regarding whether the new receptors are created within the affected dendrite or in the soma, but an observed property of LTP suggest that it is the soma. More on this after a bit.
These newly minted receptors are then transported (usually via microtubules) to the synaptic membranes of the specific dendrite that triggered this cascade, not any others. The plastic change is limited to the dendrite that was subjected to high frequency stimulation. This dendrite receives an added boost in its responsiveness (in addition to e-LTP changes) to future stimuli through the addition of new receptors generated through protein synthesis.
This characteristic of LTP, which limits the plastic effects to the triggering dendrite demonstrates LTP Selectivity.
But what happens if during this high frequency stimulation, another separate dendrite is experiencing a sub-critical stimulus? Turns out that this other dendrite experiences LTP as well. This argues for soma production of the new receptors, and the presence of a local impulse-driven cofactor that promotes transport of the new receptors since the level of stimulation in the other dendrite is too weak to trigger e-LTP cascades. This phenomenon is called LTP Association. The potential relationship of LTP association to certain cognitive biases will be a topic for the future.
This is LTP in a nutshell. LTP results in enhanced receptor response to future stimuli and more receptors. LTP appears to be a key component of the neuroplastic changes that result in the creation of new memories. But as you might expect, there is a lot more to it... Next time? The creation of new synapses and the deregulation of others. After that, the modulation of these processes by other neurotransmitters, the role of nucleic acids, then it's off to the anatomy of the brain.