Monday, March 25, 2013

Guest Post: AMPA Receptors are not Necessary for long term potentiation

Today's post is brought to you by @BabyAttachMode, who is an electrophysiologist and blogger. Today we are blog swapping! I have a post over at her blog and her post about AMPA receptors and LTP is here. So enjoy, and when you're done reading about the newest advances in synaptic plasticity here, you can head over to InBabyAttachMode and read about my personal life.
AMPA Receptors are not Necessary for long term potentiation

Science is most interesting to me when you’re testing a hypothesis, and not only do you prove the hypothesis to be false, but you discover something unexpected. I think that happened to Granger et al. They were trying to find which part of the AMPA receptor is necessary for long-term potentiation (LTP), the process that strengthens the connection between two brain cells when that connection is used often. Indeed they find that AMPA receptors are not necessary at all for LTP, which is very surprising given the large body of literature describing how the GluA1 subunits of the AMPA receptor, through interactions with other synaptic molecules that bind to the intracellular C-tail (the end of the receptor that is located inside the cell), are inserted into the synapse to induce LTP.
LTP (source)
The authors made an inducible triple knock-out, which means that they could switch off the genes for the three different AMPA receptor subunits GluA1, GluA2 and GluA3. This way, they ended up with mice that had no AMPA receptors at all. The authors were then able to selectively put back one of the AMPA receptors, either the entire receptor or a mutated receptor. By inserting mutated receptors, for example a receptor that lacks its intracellular C-tail that was thought to be important for insertion of the AMPA receptor into the synapse, they could then study whether this mutated receptor was still sufficient for induction of LTP.

Surprisingly, they found that deleting the C-tail of the GluA1 subunit does not change the cell’s ability to induce LTP. Even more so, they showed that you don’t even need any AMPA receptor to still be able to induce LTP; the kainate receptor (another type of glutamate receptor that has never been implicated in LTP) can take over its job too.

Figure 6C from Granger et al. (2013). Kainate receptor overexpression can lead to LTP expression, without the presence of AMPA receptors.

About this surprising discovery the authors say the following:
"These results demonstrate the synapse's remarkable flexibility to potentiate with a variety of glutamate receptor subtypes, requiring a fundamental change in our thinking with regard to the core molecular events underlying synaptic plasticity."
Of course if you say something like that, the main players in the LTP field will have something to say about it, and they did. Three giants in the field of synaptic physiology commented in the journal Nature, but their opinions differed. Morgan Shang called it "a step forward", whereas Roberto Malinow and Richard Huganir called it "two steps back", saying that LTP without AMPA receptors can only happen in the artificial system that the authors of the paper use to study this. They expect that cells lacking all three AMPA receptors will look so different from the normal cells that the results are difficult to interpret.

Either way, this paper opens new views and questions to how LTP works, and whether AMPA receptors are as important as we thought.

ResearchBlogging.orgGranger AJ, Shi Y, Lu W, Cerpas M, & Nicoll RA (2013). LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature, 493 (7433), 495-500 PMID: 23235828
Sheng M, Malinow R, & Huganir R (2013). Neuroscience: Strength in numbers. Nature, 493 (7433), 482-3 PMID: 23344353


  1. A colleague just walked in and said 'That thing about AMPA receptors not being needed for LTP ... That's Scary!"

  2. Right, but then what do you do about all the overwhelming evidence that shows that AMPAR are involved in the expression of LTP? This evidence is clearly not suddenly untrue or wrong. The data is still valid. What the authors in the Granger paper fail to do is to provide an alternate explanation for all the existing data, rather, they show that if you push your experimental system in a given direction, you can get it to act in a certain way, probably in a way that is less physiological than the already unphysiological methods of inducing LTP.

    1. I totally agree with your criticism. When I talk to my PI about inducing LTP he says that it actually stands for "Less Than Physiological" and forbids me to do those experiments ;-) I think that the bottom line of this paper is that if you push the system enough, you can get potentiation even with other receptors than AMPA receptors, which I think is still interesting, because that might mean that the mechanism for insertion or movement of the receptors can apparently also be used for other receptors.
      Or maybe it shows that LTP is fake in itself.

    2. Your PI is dumb.

  3. I think the paper suggests that the mechanism of LTP is primarily a remodeling of the postsynaptic density to make more slots for AMPARs rather than a direct AMPAR trafficking mechanism. If there are more spots for AMPARs, it doesn't matter which subtypes are there. Usually GluA1 is the primary subunit required for LTP because this is the subunit that is at the highest levels on the surface so is most likely to fill these new slots.