“As you know, in most areas of science, there are long periods of beginning before we really make progress.” – Eric Kandel
In a typical maze experiment, a hungry rat enters a moderately complicated maze, in which it does its best to find a “reward room” with food. After some guesses, the rat finds its way, consumes the food, and is returned to the entrance of the maze. From then on, the rat makes fewer bad guesses and finds the food faster after each round. Eventually, it completely masters the maze layout and finds the perfect route every time. To explain this improvement, scientists have coined the term reward reinforcement, which essentially suggests that the reward that the rat collects at the end reinforces its correct choices, until it eventually learns a perfect route. This model may sound very simple, but is it?
The rat collects its food in the reward room, not during the navigation or decision-making. Therefore, the brain’s reward system does not turn on until the end of each run. How, then, does the reward system backtrack in time and selectively reinforce choices made in the past? If we had the ability to look into the rat’s brain and watch the activities of the synapses (the connections between neurons), we would find, as the rat navigates through the maze, millions of synapses flash on and off, while millions more remain silent. How does the brain keep track of this enormous, evolving constellation of synaptic activity, so that only the appropriate ones can be tuned up and down by the reward in the end?
One way to solve this problem is to have a logging system, in which individual synapses log their activity over time, like hourglasses that are flipped on (to let sand through) only when their corresponding synapses are active and flipped upside-down when inactive. In this way, when the reward arrives, the active synapses can be singled out by reading the hourglasses. This idea is called synaptic tagging.
What is the nature of this activity tag? One strong candidate arises from work done by Kausik Si (pronounced “See”) and Nobel Laureate Eric Kandel. It’s an RNA binding protein called CPEB (not to be confused with CREB, which is a different protein that is also important for memory). CPEB is turned on in active synapses and is necessary for maintaining long-term memory in different animal species1,2.
How does CPEB tag synaptic activity? Si and Kandel’s answer initially flabbergasted the entire neuroscience community: it is a prion. Prions are most famous for causing spongy brains in the mad cow disease. Many proteins can be prions, as long as they spontaneously form strong aggregates (i.e. clumps) and expand the aggregates by converting single proteins into the self-aggregating form. Proteins involved in many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, have recently been thought to resemble prions. However, the CPEB aggregates are not the harbingers of disease but rather the functional essence of the protein. The aggregation of CPEB only happens in active synapses, and blocking the aggregation, either by antibody neutralization or by mutation of the gene, reduces synaptic plasticity and the animal’s ability to form long-term memory3–5.
Initial insights into the function of CPEB come from the observation that its aggregate binds RNA4. A recent paper by the Si group proposes that the aggregation of CPEB promotes memory formation by switching CPEB’s function from suppressing to promoting protein translation6. This switching phenomenon depends on CPEB’s ability to recruit other protein complexes to modify the stability of RNAs.
Is CPEB the only mechanism for synaptic tagging? Probably not. Studies of CPEB indicate that it is essential for long-term memory, on the timescale from hours to days. However, tagging synapses on a shorter time scale is also needed to explain problems such as delayed reinforcement (described above). There is strong evidence that synapses can be tagged and tuned concertedly within a much shorter timeframe, although scientists do not yet know how this happens7. When this mystery is revealed, another gasp of surprise will be heard reverberating across the neuroscience community.
- Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115, 893–904 (2003).
- Keleman, K., Krüttner, S., Alenius, M. & Dickson, B. J. Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nat. Neurosci. 10, 1587–93 (2007).
- Majumdar, A. et al. Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148, 515–29 (2012).
- Si, K., Lindquist, S. & Kandel, E. R. A Neuronal Isoform of the Aplysia CPEB Has Prion-Like Properties. Cell 115, 879–891 (2003).
- Si, K., Choi, Y.-B., White-Grindley, E., Majumdar, A. & Kandel, E. R. Aplysia CPEB Can Form Prion-like Multimers in Sensory Neurons that Contribute to Long-Term Facilitation. Cell 140, 421–435 (2010).
- Khan, M. R. et al. Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator. Cell 163, 1468–1483 (2015).
- He, K. et al. Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. Neuron 88, 528–538 (2015).