Memory: From Molecular Mechanisms to Clinical Applications

Abstract

Memory is a phenomenon that has fascinated scientists as well as writers, philosophers, and common people since the beginning of mankind. As has been repeatedly underlined, memory is both incredibly powerful and fragile; we all have memories that date back to our infancy, and at the same time, we can forget what we did yesterday or where we parked our car this morning. For the biologist, memory is a remarkable feature of the nervous system, and its unique properties have attracted the interest of scientists from every field, ranging from molecular biologists to psychologists and even to physicists and mathematicians. Ever since the identification of the synaptic contacts as the sites of communication between neurons, the prevalent notion for the cellular mechanisms underlying the storage of information in the CNS has been some form of activity-dependent modification of synaptic efficacy. This idea, already present in Ramon y Cajal’s writing, was further popularized by Hebb (1), and, many years after Hebb’s death led to the now famous concept of hebbian synapse (2,3). Unfortunately, the search for the cellular mechanisms of memory got a bad reputation following a series of experiments attempting to demonstrate that, while the genes held the memories of the species, proteins were the repositories for the memories of the individuals. These attempts resulted in the infamoustransfer of memory experiments, in which extracts from trained worms were fed to naive worms or brain extracts from trained mice were injected into naive mice (4-7). While experimental psychologists were making great progress at providing a classification of various forms of memory (8), the search for the cellular mechanisms remained limited to the study of some simple systems such as the sensitization of the gill withdrawal reflex in Aplysia (9) or the acquisition of classical conditioning in Hermissenda (10). However, an important discovery, published in 1973, forever changed our views of the cellular mechanisms of learning and memory (11). After failing to find synaptic plasticity in neocortex as a Ph.D. student, Bliss (12) moved to Per Andersen’s laboratory. There, Bliss and Lomo discovered a form of activitydependent modification of synaptic plasticity at hippocampal synapses that exhibited several features expected of a cellular mechanism of learning and memory. They called it long-lasting potentiation, but it soon became known and referred to as long-term potentiation or LTP. Over the last 30 years, this phenomenon has become the epicenter of the discussions related to the mechanisms of learning and memory, and, as we will discuss below, has generated a wealth of information regarding not only the basic mechanisms of learning and memory but also the first rationale design of new molecules directed at improving learning disabilities resulting from diseases or old age. In this chapter, we will first review the features of LTP, and discuss why these features are well suited for a learning mechanism. We will then summarize the current hypotheses that have been proposed to explain LTP, and to account for the links between LTP and learning and memory (Fig. 1). This will be followed by a review of the properties of positive AMPA receptor modulators, the ampakines, and of the studies indicating that they facilitate LTP formation and improve learning in a variety of tasks. The review will conclude by a brief survey of the various clinical trials currently evaluating these molecules for selected indications.