Learning and Memory, Part I: Brain Regions Involved in Two Types of Learning and Memory

As presented in the previous two columns on fragile X syndrome, the absence of fragile X mental retardation protein in fragile X disrupts the transport of messages (messenger RNAs [mRNAs]) along dendrites and their translation into proteins. This is because one of the functions of fragile X mental retardation protein is to normally repress local translation of mRNAs at sites adjacent to synapses, and in its absence, mRNAs are inappropriately translated. Researchers also found that activating a specific subtype of glutamate receptor (metabotropic glutamate receptor 5 [mGluR5]) is an important signal that initiates the translation of mRNAs at synapses. These two observations were put together to formulate a new hypothesis, called the BmGluR hypothesis of fragile X syndrome.[ It suggests that reducing mGluR5 signaling might reduce the excessive translation of synaptic proteins in fragile X. One target of therapeutic intervention therefore is to develop mGluR5 antagonists and try these drugs first in animal models of fragile X syndrome and eventually in patient populations. This column and the next take the story further to discuss some of the molecular events that actually occur inside neurons during the development of synaptic plasticity and how these changes in synaptic strength can be measured in the laboratory. Among the topics that we cover are long-term potentiation and some of the mechanisms thought to explain why Bneurons that fire together wire together.[ We begin with a biking accident. Approximately 70 years ago, in a small town outside Hartford, Connecticut, a young boy was riding his bicycle when he fell off and hit his head. Soon thereafter, he developed a seizure disorder. The story of H.M. has been told and retold over the years and is only briefly summarized here. Initially, H.M. was successfully treated with anticonvulsant medications, but his seizures continued to get worse and became profoundly disabling over the next decade. He had difficulties finishing school and maintaining employment. In 1953, when H.M. was 27 years old, in an attempt to control the seizures, a surgical procedure was proposed to remove from within the medial temporal lobes what was believed to be sclerotic tissue that had formed after the head trauma. Dr. William Scofield performed bilateral medial temporal lobotomies that removed the hippocampi, the parahippocampal cortex, and parts of the amygdala. After the surgery, H.M.’s seizures were much better controlled. However, it was soon apparent that he had also lost the ability to form new declarative memories. These types of memories are those that one is conscious of and can talk about. H.M. is still alive today and has met with the psychologist Dr. Brenda Milner for a hundred times, yet he retains no memory of her and has to be introduced each time they meet. He retains new information for only minutes at a time and has lost the ability to turn these short-term memories into longlasting memories, a process called consolidation. It is important to realize that H.M. retains and can recall many memories formed before surgery and occasionally retains new information for longer periods but only with excessive practice. These seminal studies by Scoville and Milner established the role of the hippocampus in the consolidation of declarative memories. Scofield never performed the surgery again and, in fact, spent much of his time traveling the world to lecture about the dangers of this type of bilateral procedure. The basic Assistant Editors C L I N I C A L I M P L I C A T I O N S O F B A S I C R E S E A R CH Paul J. Lombroso,M.D.,Marilee P. Ogren, Ph.D.