Thursday, February 9, 2012

LTP and LTD at the same time? Adventures in Functional Compartmentalization

On Monday we talked about LTP and LTD on a basic level, today we are discussing how they interact with each other.  In a recent Open Access paper, Pavlowsky and Alarcon ask the question: Can some synapses on a neuron strengthen while at the same time others weaken?  And if so, how do the two processes interact with each other?

neurons firing (source)

First let's get some background.  Synapse strengthening (LTP) and synapse weakening (LTD) both require new proteins to be synthesized at the soma* (*in this particular situation, sometimes they don't require it, but those details are too deep to dive into here).  So what happens if LTP is induced at some synapses and LTD is induced at others on the same neuron?  There are three possibilities:

  1. They compete for protein synthesis at the soma, one using up all the precious protein synthesis machinery and impairing the development of the other
  2. They cooperate, one starting up the protein synthesis engine at the soma so it's ready to go, helping the other.
  3. They don't interact and just do their own thing like normal.

To determine which of these possibilities actually happen in a neuron, Pavlowsky and Alarcon induce LTP and LTD on the same cells, but in different places. 

Showing stimulation on the same side of the soma
From Figure 2 Pavlowsky and Alarcon 2012

 They induced LTP in one spot (S2) and then induced LTD in another (S1).  And lo and behold! the LTP happening first prevented the LTD (favoring the compete hypothesis above).

So this shows that LTP and LTD compete in the neuron.  But what are they competing for?

There are two steps in protein synthesis where LTP and LTD might compete: translation (getting a protein from an mRNA) and transcription (creating more mRNA from the DNA). 

To test whether translation or transcription is important for this competition, the researchers induced LTP at S2 in the presence of either a translation blocker (anisomycin) or a transcription blocker (actinomycin-D).  Then they washed away the blocker and induced LTD at S2.

From Figure 6 Pavlowsky and Alarcon 2012

 The translation blocker allowed for subsequent LTD at S1 (top left of figure), while the transcription blocker didn't (top right of figure), even though both prevented the initial LTP at S2 (bottom panels of figure).  This is evidence that the translation phase of  protein synthesis is important for determining which form of plasticity gets induced (LTP or LTD). 

So what does all this mean? The results support the compete hypothesis, that the first plasticity induction (LTP or LTD) gets dibs on most of the plasticity-related protein synthesis machinery and prevents the other from happening.  However, if the first induction can't  access the protein translation machinery (because it is blocked with anisomycin), then the second induction is able to use it just as it normally would. 

The authors do a thorough job investigating this phenomenon, testing different time intervals between LTP and LTD induction, testing location of the stimuli, and have some interesting discussion about what this might mean for learning and memory.  If you are interested in the details, I highly recommend this paper, it's in PLoS One, so it is open access.

copyright TheCellularScale Pavlowsky A, & Alarcon JM (2012). Interaction between Long-Term Potentiation and Depression in CA1 Synapses: Temporal Constrains, Functional Compartmentalization and Protein Synthesis. PloS one, 7 (1) PMID: 22272255

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