Yale scientists have pinpointed a protein that is crucial to learning and memory. Called TARPγ-8, it is part of a molecular cascade in mice that leads to long-term potentiation (LTP), the process by which connections between neurons, called synapses, grow stronger. LTP has long been considered the cellular basis for learning and memory but not all of its molecular players have been worked out. Here’s what lead researcher and neuroscientist Susumu Tomita said about his team’s findings, published in the October 5 issue of the journal Neuron.
Kavli Institute for Neuroscience (KIN): Neuroscientists described LTP about 40 years ago. Why has it been so difficult to figure out its molecular basis?
Tomita: I think the reasons are twofold. One, there are likely many different molecular mechanisms involved in complex processes such as learning and memory; and two, it’s difficult to identify the specific biochemical changes in neurons that enable learning or the formation of new memories. Some of the proteins that regulate learning and memory act on at least 100 other molecules, modifying their biochemistry in important ways. That makes it hard to pinpoint which of those target molecules is critical to a given brain process.
To circumvent this issue, we took a bottom-up approach. We focused on a molecule called TARPγ-8 that we know controls synaptic activity, and then we identified how it is modified by other proteins in the cell, in particular CAMKII, an enzyme that adds a biochemical tag to TARPγ-8. We also showed in genetically altered mice that tampering with TARPγ-8 impairs learning and memory.
KIN: Your work has helped to fill a gap in our knowledge about LTP. What would you still like to understand about it?
Tomita: Several questions about LTP remain. For example, what specific roles does LTP play in learning and memory? In other words, does the increase in synaptic activity mediated by LTP help to acquire information transiently in the brain during learning or to store information stably in the brain during memory formation? And how do the biochemical changes to TARPγ-8 increase synaptic activity, strengthening the communication between neurons? Furthermore, it is important to emphasize that in our genetically altered mice, we measured a 60% reduction in LTP, along with impaired learning and memory, but 40% of LTP remained. We’d like to explore what other mechanisms are involved in LTP that, to some extent, allowed the mice to keep learning and forming even when TARPγ-8 was inactivated.
KIN: Other brain researchers have shown that it is possible to implant and erase fear memories in rats by turning neurons on and off with light. Does your discovery open the door to other ways to control learning and memory?
Tomita: As you just mentioned, light has been used to inactivate and reactive memories by inducing LTD, or long-term depression, which weakens synaptic transmission between neurons, and LTP. However, it would be hard to use that approach in humans to treat memory-related disorders, such as post-traumatic stress disorder (PTSD) or dementia, because it requires risky, invasive surgery. Our identification of a biochemical substrate for learning and memory could lead to a drug for erasing memories from PTSD or enhancing memory in dementia. Furthermore, locating the substrate of LTP gives us an opportunity to identify the primary neurons involved in learning and memory. It might then be possible to boost learning and memory by stimulating those neurons
Tomita is a professor of Cellular and Molecular Physiology and of Neuroscience and a member of the Kavli Institute for Neuroscience at Yale. His lab studies the molecular machinery involved in synaptic transmission and plasticity. The work was conducted with Pablo Castillo of Albert Einstein College of Medicine and Marina Picciotto, a professor of Psychiatry at Yale who is also on the Steering Committee of the Kavli Institute for Neuroscience.