In 1942, Jorge Luis Borges wrote about a boy named Ireneo Funes who, following a horseback riding accident, developed a phenomenal memory. He was able to recall entire volumes (in his non-native language) and recite them fluidly. In contrast to others with hypermnesia (see The Mind of the Mneumonist by A.R. Luria), what made Funes’ memory particularly curious was his inability to forget and the specificity of his memories. When he remembered, for example, a cloud in the sky, he not only remembered the specific cloud, but the time he viewed it, the direction of the wind, if he was hungry, what smells were in the air, etcetera. He even created distinct memories each time he saw an object at a particular angle. Sage from the left would be a distinct memory from Sage from the right.
Though fiction, this 70 year old story brings to the fore an important question regarding memory formation: How do we remember some things and forget others? Surely, there is a tremendous amount of informational throughput: We have countless experiences during the course of even a single day. But why is it that we only remember a minority of these experiences?
Deep in the heart of Missouri, Kausik Si and his team are researching just this. To phrase the question from a more biological standpoint: “How does the altered protein composition of a synapse persist for years when the molecules that initiated the process should disappear within days?” (Majumdar et al., 2012; 515)
Proteins are recycled with a certain regularity (mostly through proteolytic processing by the lysosome). Proteins that stick together and oligomerize (think of legos being stacked together) can be immune to such degradation (a child would have a harder time eating a stack of legos than they would an individual piece). This process has been explored in a pathological context – for example: beta-amyloid plaques and Alzheimer’s disease – but what if it has physiological relevance in a biological context?
Based upon previous studies with the sea slug (Aplysia), Si et al. hypothesized that oligomers of the Orb2 protein could provide a substrate for the persistence of memory.
Through careful biochemical experiments, they determined that Orb2 was expressed as a monomer (one lego) and an oligomer (multiple legos). These were often hetero-oligomers comprised of splicing variants of the orb2 transcript (different color legos). In fact, it seems as though the smaller Orb2a variant, which is very sparsely expressed, plays a catalytic role in the oligomerization of Orb2b. Disruption of Orb2a expression had no effect on memory acquisition, however it showed a marked defect in memory retrieval after 48 hours – thus suggesting that Orb2a expression, and subsequent oligomerization of Orb2, plays a causal role in the persistence of memory.
They performed two separate behavioral memory tests to show that this is a generalizable phenomenon. Let’s focus on the first one, because it is first and also ripe for humorous extrapolation.
In the “Male Courtship Suppression” task, males are exposed, repeatedly, to unreceptive females (guys, I think you can relate). Over time, these males, discouraged and probably in the throws of a melanogaster-existential crisis, suppress their haughty courtship and stand down. However, flies with a mutation in the Orb2a isoform had no difficulties remembering being spurned in the first 36 hours (figure 7c). But within 48 hours, they were back on the horse, pursuing the same unreceptive female (ladies, you may know the type).
This suggests that the Orb2a isoform is necessary for the persistence, and not the formation, of long-lasting memories.
While further work needs to be done to explore how these oligomers represent a memory at the level of a single neuron, as well as in a network of neurons, it provides a novel pathway completely distinct to the well-studied activity-dependent immediate early genes. I encourage you all to come see Doctor Kausik Si’s talk at 4PM in the Large Conference Room in the Center for Neural Circuits and Behavior!
Sage Aronson is a first-year Neurosciences student currently rotating in Roberto Malinow’s lab. He spends an inordinate amount of time on a bicycle and has a peculiar fondness for the word “spelunking.”
Borges, Jorge Luis. “Funes the Memorius.” Ficciones. Buenos Aires: Emecé Editores, 1956. N. pag. Print.
Majumdar A., Erica White-Grindley, Huoqing Jiang, Fengzhen Ren, Mohammed “Repon” Khan, Liying Li, Edward Man-Lik Choi, Kasthuri Kannan, Fengli Guo & Jay Unruh & (2012). Critical Role of Amyloid-like Oligomers of Drosophila Orb2 in the Persistence of Memory, Cell, 148 (3) 515-529. DOI: http://dx.doi.org/10.1016/j.cell.2012.01.004