What Role Does Long Term Potentiation Play in the Brain?
Long Term Potentiation vs. Long Term Depression
In 1973, a major development in the hippocampus was uncovered by Timothy Bliss and Terje Lonco, when they found that after a “strong stimulation of nerve pathways” going to the hippocampus, the post-synaptic responses of those pathways were greatly amplified in their test subjects (rabbits, with electrodes delivering 10 to 100 pulses per second for up to 10 seconds) (Dowling 220, Dubuc “Long,” Rose 227).
This phenomenon became known as long-term potentiation (LTP), and it shows that “long term changes in synaptic efficacy can be induced to last for days or even weeks in single hippocampal neurons by primary stimuli.” And these neurons can also undergo long-term depression (LTD), which is the opposite result. Here, instead of an amplified signal we get a diminished one that can last for days or even weeks (Ibid).
And somehow, these two processes play a role in long-term memory formation, but the details are still quite murky. As for short –term memories, they must be stored elsewhere as Patient H.M. and others has demonstrated. And as for how memories are stored in neurons or their circuity, well that is the big question that remains a mystery (Dowling 221-2).
And if that wasn’t enough, that is tied to other mysteries of the hippocampus. New neurons are only created here, but they have a short lifespan whose number decreases with age but increases with exercise. Also unusual are place cells that activate depending on where you are at. New ones can be made as well as lost and demonstrates the temporal abilities of the brain (223).
Synapses and Long-Term Potentiation
In establishing LTP, a presynaptic axon sends a neurotransmitter signal upon activation. This neurotransmitter normally interacts with a receptor protein on the post synapse, causing a voltage drop and a new signal to be sent. But with LTP, glutamate interacts with N-methyl D-aspartate (NMDA) and nonNMDA channels. The non-NMDA channels allow Na+ to enter, depolarizing the cell (Dowling 223-5, Dubuc “Long”).
But the NMDA is where the LTP action is. If a cell is at normal potential voltage, then the glutamate sticks to NMDA and no action occurs as Mg2+ prevents it. But if something else depolarizes the cell, then we are good to go (Ibid).
This is because as the cell becomes more positive, it repels Mg2+ and leaves the channel unblocked. Na+ and Ca2+ can enter. That calcium is key to the process, for it binds to calmodulin (“calcium-binding protein”) when can activate many kinases and change their function. How the three known kinase types impact the postsynaptic response isn’t clear still (Dowling 225, Dubuc “Long”).
Also interesting is a presynaptic response during LTP, seemingly causing it to release more neurotransmitter. It does seem like effect leading to further cause but it’s likely a feedback system (Ibid).
Short Term vs Long Term
The above was the short term LTP process also known as the establishment phase, while the long term one also known as the maintenance phase is a bit more involved. It still involves that calcium ion and the calmodulin, but now if enough of each is present then it mixes with adenylate cyclase, allowing ATP to become cyclic adenosine monophosphate or cAMP (Dowling 226, Dubuc “Long”).
This then mixes with protein kinase A(PKA), which “leads to the phosphorylation of the transcription factor CREB (the cAMP response element binding) protein.” This leads to DNA changes in expression to RNA, meets ribosine to create a new protein which can make new channels (Ibid).
LTP and Memory
Okay, so far there is no ties back to memory. Enter the Morrie water maze test, which demonstrates ties between hippocampal LTP and spatial learning in mice. The test was named after R.G. Morrie (University of Edinburgh) who placed mice in a water tank and trained them to respond to spatial cues as to finding a platform. These were done as to be independent of the orientation of the tank, and even if the platform was removed the mice still took the cues to try and find it. But if the NMDA receptors were “blocked pharmacologically” then the platform location was unable to be found, despite the training undergone (Dowling 227-8, Dubuc “Long”).
And in a further test to demonstrate short term vs long term LTP, PKA or CREB was removed from mice who trained to do the task. They were still able to perform the test, but only for up to 1 hour afterward. After that, the mouse swam around randomly and stopped using the visual cues to help it. It was as if the mice were “unable to convert early memories into more persistent ones.” It was later found that general protein synthesis inhibitors also result in this behavior (Ibid).
Short Term Memory
People with hippocampus-related injuries usually have great short-term memory but it quickly goes away. So, where does it originate? It has to be someplace beyond the hippocampus. Some evidence does point to a weak link between short term LTP and short-term memory. Instead, it’s more likely that a mix of short and long term LTP contributes to the formation of long-term memory (Dowling 229, Dubuc “Short”).
The time duration these events also sheds light, for short term LTP can last for hours while short term memory usually is gone after a few minutes. Long-term memory is attached to structural changes while short term maybe is about temporary chemical scenarios. Of course, the level of interest in the topic directly contributes to something being stored in long term memory, as well as something known as Papez’s circuit, which involves the limbic system impacting the hippocampus and temporal lobe (Ibid).
Research points to the number of cycles run through this circuit as being correlated to the chances of something remaining in long term memory, likely due to structural changes being reinforced through loops of the information, independent of the hippocampus. This is why damage to it prevents new long-term memories from forming but doesn’t inhibit short-term memory nor access to an already established long-term memory. Instead, certain cortical regions will become encoded with it (Ibid).
But where is it happening if not in the hippocampus? Lots of research points to the dorsolateral prefrontal cortex, but much debate exists as to its exact role. Does it do the coordinating or the actual storage itself? Its role with the hippocampus remains to be fully fleshed out. Because the hippocampus helps coordinate long-term memories, tying that to the short-term is crucial to our understanding of both short term and long-term memories (Dubuc “Short”)
Works Cited
Dowling, John. Understanding the Brain. W.W. Norton & Company, New York, NY. 2018. Print. 219-229.
Dubuc, Bruno. “Long-Term Potentiation.” Thebrain.mcgill.ca. Canadian Institutes of Health Research. Web. 26 Apr. 2021.
--- “Short-Term Memory.” Thebrain.mcgill.ca. Canadian Institutes of Health Research. Web. 26 Apr. 2021.
Rose, Steven. The Making of Memory. Doubleday, New York. 1992. Print. 181-4, 189-195, 215-221, 224-8.
© 2024 Leonard Kelley
