Remember to forget

April 1, 2014

Yes, forgetting is essential! In order not to overload your brain with “useless” information from the past you need to be able to forget. But how does forgetting work? Synapses connect neurons in the brain and it is thought that an altered neuronal structure (read: different wiring or less wiring) leads to forgetting. While a lot of time, money and careers are invested into the question how synaptic networks are formed, it is not very clear how the complexity can actually decrease. Assuming that a reduced synaptic “landscape” is equal to the well-known process of forgetting, it is therefore not very much known about this process. Although not te first of its kind, a recent paper addresses this issue and proposes a molecular mechanism which is mainly based on the regulation of the actin cytoskeleton via a post-transcriptional mechanism. And the evidence seems strong! The model organism used here are the C. elegans worms that can actually be trained to avoid a certain taste because they were starved of food when they were in contact with it for the first time. Remembering and forgetting this Pavlovian training by the worms can then be used as a proxy for memory function. As already mentioned, the major player in the competition between memory formation and forgetting is the rate at which synapses are formed and degraded. An already previously described and neuronal active protein called MSI-1 is proposed here to be responsible for the degradation part by inhibiting the translation of at least three mRNA types (arx-1, 2 and 3) who´s protein products would normally from the Arp2/3 complex. This complex is normally responsible for remodeling the actin skeleton of the synapses by the induction of actin branching. MSI-1 therefore prevents the Arp2/3 complex formation and thereby leads to decreased synaptical structure retention. In other words: MSI-1 increases the tendency for synapses to disappear, which might be one factor to answer the question why we forget things. This interplay is further strengthened by the authors finding that the deletion of the add-1 gene (responsible for actin capping and therefore stabilization) leads to memory loss. However, this phenotype could be reversed when msi-1 is deleted at the same time. As a consequence, add-1 and msi-1 must both be involved in memory formation and retention, but with opposing functions.

An unresolved question, however, remains how MSI-1 is “activated” to suppress arx mRNA translation. It is likely that forgetting is a neuronally regulated and controlled process, just like memory formation. The authors propose that the glutamate receptor GLR-1  might play a role in this process because it´s expression is exclusively increased in the MSI-1 positive neurons during learning. On the contrary GLR-1 is also required for MSI-1 function and therefore memory loss. How the upstream regulator GLR-1 can influence these two opposing events at the same time therefore remains an open question for future studies. Another interesting and open question is the link between the AVA neurons in which MSI-1 was predominantly found and neurons in the gut of the worms in which MSI-1 was also found. Can this link be explained by the food/starvation related setup of the experiment? And do other forms of training/memory acquisition and the resulting forgetting mechanism work differently? Furthermore, what are the effects of MSI-1 on the other numerous actin remodeling factors?

Despite these open questions, the paper presents compelling evidence for an additional molecular mechanism explaining neuronal information retention and loss. In summary and interestingly, memories seem to be regulated in a balanced way that is deeply influenced by the synaptical actin skeleton which is actively constructed, and passively degraded by the inhibition of its formation through the translation repressor MSI-1.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: