Surprisingly, the protein preferentially lodged itself in one kind of synapse. Synapses come in a few flavors, depending on whether they’re formed by so-called thin, stubby, or mushroom spines protruding from the cell. The tagged glutamate receptor migrated primarily into the mushroom-type synapses.
“I think the most important thing about this study is that it suggests that a specific type of spine may be more important for learning and memory processes than other types of spines,” says Powell.
The receptor’s “preference” for mushroom-type synapses suggests that, at least in the process of forming a fear-related memory, there is a specialized trafficking system to direct synaptic proteins to their targets. “But what sort of molecular flag gets waved to say, ‘Come up here and make your home at my type of synapse,’ is not really clear,” says Maren.
Another mystery is why the tagged receptor disappears from the synapses after 72 hours, when the memory persists much longer. Other proteins and other brain areas are almost certainly involved in forming and maintaining the memory. The amygdala in particular probably plays a key role. While the hippocampus is critical for encoding information about place–in this case, the box where the shocks were administered–the amygdala seems to tie that information to the fear response produced by the shocks.
“The hippocampus is probably not the final storage site,” says Maren. “If you really wanted to see where the long-term memory was encoded for this type of learning, you probably want to look at the amygdala.”
In previous investigations of the amygdala using similarly engineered mice, Mayford’s group showed that the same neurons are activated both when a memory is formed and when it is later retrieved. In future studies, the researchers may apply the new finer-scale approach to probe memory formation in the amygdala.
Mayford also hopes to use the new technique to elucidate the precise structure of a memory encoded by the hippocampus–in particular, a memory of the box. He plans to determine whether he can teach a mouse that’s never been shocked inside the box to fear it nonetheless. To do so, he would activate the hippocampal neurons that encode the memory of the box, and then give the mouse a shock.
If the experiment is successful, it could help explain how the box is represented within the mouse’s brain. “One of the big questions in neuroscience,” says Mayford, “is, what does it take to make a representation of the external environment?”