Getting to the bottom of memory

Phone numbers, the way to work, granny’s birthday – our brain with its finite number of nerve cells can store incredible amounts of information. At the bottom of memory lies a complex network of molecules. To understand how this network brings about one of the most remarkable capacities of our brain we need to identify its components and their interactions.

Researchers from the European Molecular Biology Laboratory’s (EMBL) Mouse Biology Unit in Monterotondo, Italy, and the Universidad Pablo de Olavide in Sevilla, Spain, now for the first time investigate the molecular basis of memory in living mice. The study, which appears in the current issue of Learning and Memory, identified a molecule that is crucially involved in learning and singled out the signaling pathway through which it affects memory.

Our sense organs inform our brain about what happens around us and brain cells communicate this information between each other using electrical signals. These signals become stronger the more often a cell experiences the same stimulus allowing it to distinguish familiar information from news. In other words a cell remembers an event as an unusually strong and long-lasting signal. This phenomenon called long-term potentiation (LTP) is thought to underpin learning and memory and its molecular basis is being investigated intensively.

“It is difficult to study a dynamic process like memory in the test tube,” says Liliana Minichiello, whose group carried out the study at EMBL’s Mouse Biology Unit in collaboration with Agnès Gruart at the Universidad Pablo de Olavide in Sevilla, Spain, who performed the behavior and in vivo recordings. “To assess if the molecular mechanisms that generate LTP also underpin memory formation you need to study a living animal while it is learning.”

Minichiello and her team combined molecular, electrophysiological and behavioural methods in a sophisticated mouse model. This new approach allowed them for the first time to start dissecting the molecular basis of LTP while simultaneously addressing effects on learning and memory. Using genetic methods they generated mouse strains with a defective version of a receptor molecule called TrkB. TrkB is found on the surface of cells in the hippocampus, an area of the brain involved in memory formation, and translates incoming signals into cellular responses. Mice with the defective TrkB, which is incapable to activate an important signaling pathway involving the protein PLCg, were no longer able to learn. At the same time the LTP that normal hippocampal cells generate in response to familiar stimuli was abolished.

“TrkB and the PLCg activated signaling pathway are central to both LTP and learning. For the first time we have been able to prove that LTP and learning do in fact have a common molecular basis,” says José Delgado-García from the University of Sevilla.

For the future Minichiello and her lab are aiming to gain an even better understanding of TrkB and its role in learning and memory. Their research might give new impulses also to studies concerned with human memory, because underlying molecular pathways are likely to be conserved between species.