Neuroscientists at the Stowers Institute for Medical Research have discovered a major clue from a study in fruit flies - hardy, self-copying clusters or oligomers of a synapse protein are an essential ingredient for the formation of long-term memory.
The finding supports a surprising new theory about memory, and may have a profound impact on explaining other oligomer-linked functions and diseases in the brain, including Alzheimer's disease and prion diseases.
"Self-sustaining populations of oligomers located at synapses may be the key to the long-term synaptic changes that underlie memory; in fact, our finding hints that oligomers play a wider role in the brain than has been thought," Kausik Si, senior author of the study, said.
Si's investigations in this area began nearly a decade ago during his doctoral research in the Columbia University laboratory of Nobel-winning neuroscientist Eric Kandel.
He found that in the sea slug Aplysia californica, which has long been favored by neuroscientists for memory experiments because of its large, easily-studied neurons, a synapse-maintenance protein known as CPEB (Cytoplasmic Polyadenylation Element Binding protein) has an unexpected property.
A portion of the structure is self-complementary and, much like empty egg cartons, can easily stack up with other copies of itself. CPEB thus exists in neurons partly in the form of oligomers, which increase in number when neuronal synapses strengthen.
These oligomers have a hardy resistance to ordinary solvents, and within neurons may be much more stable than single-copy "monomers" of CPEB. They also seem to actively sustain their population by serving as templates for the formation of new oligomers from free monomers in the vicinity.
CPEB-like proteins exist in all animals, and in brain cells they play a key role in maintaining the production of other synapse-strengthening proteins. Studies by Si and others in the past few years have hinted that CPEB's tendency to oligomerize is not merely incidental, but is indeed essential to its ability to stabilize longer-term memory.
"What we've lacked till now are experiments showing this conclusively," Si said.
In the new study, Si and his colleagues examined a Drosophila fruit fly CPEB protein known as Orb2. Like its counterpart in Aplysia, it forms oligomers within neurons.
"We found that these Orb2 oligomers become more numerous in neurons whose synapses are stimulated, and that this increase in oligomers happens near synapses," Amitabha Majumdar, lead author of the study, said.
The key was to show that the disruption of Orb2 oligomerization on its own impairs Orb2's function in stabilizing memory. Majumdar was able to do this by generating an Orb2 mutant that lacks the normal ability to oligomerize yet maintains a near-normal concentration in neurons.
Fruit flies carrying this mutant form of Orb2 lost their ability to form long-term memories.
"For the first 24 hours after a memory-forming stimulus, the memory was there, but by 48 hours it was gone, whereas in flies with normal Orb2 the memory persisted," Majumdar said.
The study has been published in the online issue of the journal Cell.