Lack of Specific Brain Protein Causes Marked Deficits In Learning, Memory

University of Texas Southwestern Medical Center at Dallas
A protein involved in the release of neurotransmitters in the brain isessential to learning and memory in mice, researchers at UT SouthwesternMedical Center at Dallas have found. A study published today in Neuron offers the first evidence that lackof this protein – known as RIM1 alpha – causes profound deficits in thelearning process.The discovery is a major step in understanding themolecular events that underlie learning and memory – complex processes thatcan be impaired in human neuropsychiatric disorders such as Alzheimer’sdisease, mental retardation and schizophrenia.

“We found that when you delete this molecule, the mice essentiallybecome incredibly stupid,” said Dr. Thomas Südhof, director of both theCenter for Basic Neuroscience and the C. Vincent Prothro Center for Researchin Basic Neuroscience at UT Southwestern and co-author of the paper.

Researchers hope that further study of the protein’s role in learningand memory will lead to potential treatments for some neuropsychiatricdisorders. “This is the first indication that these proteins could be goodtargets for treatment of specific brain disorders,” said Dr. Craig Powell,assistant professor of psychiatry and neurology at UT Southwestern and thestudy’s lead author.

The researchers compared behaviors of normal mice to those of threesets of genetically altered mice – each of which was missing a specificprotein involved in releasing neurotransmitters. The mice lacking the RIM1alpha protein, unlike the others, lacked the ability to learn the locationof an escape platform in a pool of water despite repeated attempts overseveral days. Dr. Eric Nestler, chairman of psychiatry at UT Southwestern and seniorauthor of the study, said another notable finding was that, while the othertwo sets of genetically altered mice displayed some of the same cellularabnormalities as the RIM1 alpha mice, these other mice exhibited nobehavioral deficits.

“The brain was able to compensate for the loss of these other twoproteins, but it was not able to compensate for the lack of RIM1 alpha,” Dr.Nestler said. “That tells us that RIM1 alpha is involved in so manyimportant functions that, when it is missing, gross changes in behavioroccur.”

Proteins involved in the release of neurotransmitters are known aspresynaptic proteins. In the past, postsynaptic proteins, as opposed topresynaptic proteins, were shown to play an active role in learning andmemory. Postsynaptic proteins receive the neurotransmitters released bypresynaptic proteins.

Dr. Nestler said that some of the abnormalities in learning in themice lacking RIM1 alpha are reminiscent of symptoms commonly seen in peoplewith schizophrenia. “This could give us new insight into what’s going wrong in the brainsof people with schizophrenia – a disorder that is still not at all wellunderstood,”

Dr. Nestler said. These studies were funded via grants from the National Institute ofMental Health, The National Alliance for Research on Schizophrenia andDepression, and the Howard Hughes Medical Institute.

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