A similar long-term memory mechanism must exist across species

As abstract a concept that memory may seem to us, it is interesting to note that there are distinct biochemical phenomena underlying it. Scientists from the Stowers Institute of Medical Research in the U.S. have gained insight into the mechanism by which the brain is able to selectively retain some information as long-term memory.

Brain cells or neurons are connected to each other at points called ‘synapses’. The lifespan of a memory depends on how strong and long-lasting these connections are, which in turn depends on their chemical composition. A class of proteins called Cytoplasmic Polyadenylation Element Binding (CPEB) proteins is a key ingredient.

The unique feature of CPEB proteins is their ability to enter a ‘prion’ state where they are able to stack up to form a chain or an oligomer. But the team led by Kausik Si was curious to find out how this oligomerisation is controlled so that only the essential memories are retained.

They studied the CPEB protein in fruitflies — Orb2. In 2012, the same lab had shown that disruption of Orb2 oligomerisation impairs fruitflies’ ability to keep long-term memory.

Two forms

Si knew that Orb2 exists in 2 forms — Orb2A and Orb2B. Orb2A is more prone to oligomerisation, but much rarer. Orb2B is much more abundant but oligomerises only in the presence of an Orb2A ‘seed’. Once an Orb2A binds to the more common Orb2B, oligomerisation enters a self-sustaining phase where more and more Orb2B is added, increasing the strength of the synaptic junction.

Si inferred that the amount and location of Orb2A protein must determine Orb2’s conversion to the prion state. To investigate how the nerve cells control Orb2A quantity, Si searched for other proteins that interacted with it. They found that when a protein Tob binds to Orb2A (which is known to happen when there is an incoming nerve signal), the usually short-lived protein’s half-life is doubled, thereby increasing its abundance.

Moreover, while normal males are known to suppress their courtship behaviour upon repeated exposure to an unreceptive female, the Tob-inactivated ones persisted in their courtship. This confirmed Tob’s role in maintaining long-term memories.

A deeper look at the mechanics of the Tob-Orb2A interaction showed that the complex also contains an enzyme phosphatase, whose job it is to remove phosphates. But removal of phosphates from Orb2A was found to destabilise it.

So how is Tob able to increase Orb2A stability? “For this, Tob recruits the neuronal protein kinase Lim Kinase (LimK) to the Tob-Orb2 complex,” they said in their paper published in PLoS Biology. LimK adds phosphate to the complex, stabilising Orb2A.

Si concluded that one way the fruitfly’s brain is able to be selective in maintaining long-term memory is by regulating PP2A and LimK activity at synapses.

The scientists write that CPEB proteins have also been identified in mice and human beings. This suggests that a similar mechanism must exist across species.

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