Alteration Of Brain Protein Regulates Learning

Theresearch sheds new light on the action of reelin, a protein known to beimportant in the nervous system. During development, reelin sends cuesto migrating neurons, telling them where they're supposed to go. Inadult mice, reelin has recently been implicated in the formation ofmemories, and reduced production of reelin has been associated withschizophrenia in humans.

In a report published in the Aug.18issue of the journal Neuron, the researchers, including Dr. UweBeffert, postdoctoral researcher in molecular genetics and lead authorof the study, and Dr. Joachim Herz, professor of molecular genetics anda member of the Center for Basic Neuroscience at UT Southwestern andthe paper's senior author, studied an area of the brain called thehippocampus, which is important for learning. The researchers focusedon the interaction of reelin and two other molecules, Apoer2 and theNMDA receptor.

In the nervous system the NMDA receptor isembedded in the membrane of synapses - gaps between nerve cells - whereit is involved in receiving signals from other nerve cells. Apoer2 isanother receptor which is associated with the NMDA receptor. Whenreelin encounters the cell, it attaches to Apoer2, which then booststhe activity of the NMDA receptor by promoting a chemical modificationof the part of the NMDA receptor inside the cell. The result of thismodification is that signals being received by the nerve cell areamplified - and better reception means better learning.

Thistransition in the primary function of Apoer2, from guiding neurons inthe embryonic brain to regulating synaptic signaling, occurs around thetime of birth. A small string of amino acids, the building blocks ofproteins, gets added near one end of Apoer2 and is essential for thisnew function. Adding the new amino acids is similar to cutting a rope,splicing in a short portion, and lashing the ends in place.

Thislonger form of Apoer2 is necessary for reelin to act upon the NMDAreceptor, Dr. Herz and his colleagues found. When reelin binds to thelonger Apoer2, the NMDA receptor alters its structure and actions,resulting in the strengthening of the signals the nerve cells receive.

Whenthe researchers created mutant mice in which Apoer2 was missing thespliced portion, they found that the mice had difficulties withlearning and memory. They were slow to learn where a hidden platformwas in murky water, among other tasks, and when the electrical activityof neurons was measured in the hippocampus of these mice there was nolonger any detectable reaction to reelin.

Thus, the extra stringof amino acids in Apoer2 seems to work like a switch that patches thereelin signal through to the NMDA receptor and, thereby, plays acentral role for learning and memory in the whole animal.

Inaddition to reelin, Apoer2 binds to a protein called ApoE. One form ofthis molecule, called ApoE4, has been shown to substantially increasethe risk of Alzheimer's disease in older people. Understanding howApoE4 functions in the brain and interacts with ApoE receptors, such asApoer2, is critical for gaining further insight into the mysteriousmechanisms that cause this debilitating neurodegenerative disease, Dr.Herz said. The loss of synapses that occurs in Alzheimer's disease isthe primary cause for the dementia in the afflicted patients.

"Our findings put ApoE receptors at the heart of the matter," said Dr. Herz.

OtherUT Southwestern researchers involved in the study were Dr. RobertHammer, professor of biochemistry; Dr. Wei-Ping Li, assistant professorof cell biology; Andre Durudas, student research assistant in internalmedicine; and Irene Masiulis, student research assistant in biophysicsand molecular genetics. Researchers from Vanderbilt University, BaylorCollege of Medicine and the Center for Neuroscience in Freiburg,Germany, also participated.

The work was supported by theNational Institutes of Health, the Alzheimer's Association, theWolfgang Paul Award of the Alexander von Humboldt Foundation, the PerotFoundation, the American Health Assistance Foundation, the HumanFrontier Science Program, the Canadian Institutes of Health Researchand the Deutsche Forschungsgemeinschaft.