Genetics of Childhood Disorders: LIII. Learning and Memory, Part 6: Induction of Long-Term Potentiation

Abstract

The last several columns have discussed the organization of human memory. The discovery of different types of memory has come from studies of human neurological patients with deficits in some forms of memory while others are preserved. For example, the memory for a particular motor skill or the ability to learn a new motor task may persist even though an individual has lost the ability to learn new faces, names, or recent events. A particularly striking example of this is the case of H.M., perhaps the most well-studied individual in the field of learning and memory. H.M. fell from a bicycle as a child and developed intractable seizures as an adolescent. In an effort to control his seizures, bilateral resections were made of his hippocampus and the medial aspect of his temporal lobes. Although his seizures abated, H.M. lost the ability to remember new information for more than a few minutes. However, H.M. was still capable of learning new motor tasks. As a result of these studies, neurobiologists came to the conclusion that the hippocampus is critically involved in translating short-term memories into long-term memories. A tremendous amount of research has been devoted to understanding the underlying molecular mechanisms that are responsible for this ability. A prominent characteristic of synapses is their capacity for plasticity, reflected as increases or decreases in the efficiency of transmission. For nearly three decades, the effort to understand how synapses encode memories has focused mainly on one form of synaptic plasticity, long-term potentiation (LTP), with the majority of studies being conducted in the hippocampus. The persistent increase in synaptic strength observed in LTP has several characteristics that one would expect of a fundamental mnemonic process. Before we look at an example of an experiment that examines LTP, we will review the neuroanatomy of the hippocampus. The hippocampus is a C-shaped structure that is tucked beneath the neocortex. It has a relatively simplified architecture and is called the archicortex to distinguish it from the more complex laminated structure found in the neocortex. The hippocampus is divided into two major parts: the dentate gyrus and the CA fields. CA stands for “cornu ammonis” or “Ammon’s horn.” The cells within the dentate gyrus are called granule cells and form a single layer of cells, whereas those of the CA fields are pyramidal neurons that also form a single monolayer. The neuronal circuitry of the hippocampus is characterized by a trisynaptic pathway (Fig. 1A), with glutamate serving as the neurotransmitter at all three synapses. The first set of synapses is made by the incoming projections that originate in the entorhinal cortex and provide excitatory synaptic inputs to the granule cells in the dentate gyrus (perforant pathway). The granule cells then send their projecting, excitatory axons (mossy fibers) to make the second synaptic connections on the dendritic arbors of pyramidal neurons of the CA3 subregion. The CA3 neurons in turn send one branch of their excitatory projections to the pyramidal neurons of the CA1 subfield (Schaffer collaterals). There are several reasons why this region is the most heav