In the July 8 issue of Current Biology, researchers at the University of California, Los Angeles, and Kyoto University, Japan, reveal that mice carrying a mutated version of the Notch gene suffer from spatial learning and memory defects. These findings are significant for the Alzheimer's community because g-secretase, the proteolytic enzyme that processes amyloid b precursor protein, also cleaves Notch.
Activation of Notch, a membrane-bound receptor, by various ligands including Delta and Jagged (see ARF related news story) sets off a signal transduction pathway that results in transcriptional gene activation. Mutations in this pathway have been linked to various developmental defects. Some, such as Alagille and Cadasil syndromes, are linked to mild mental retardation and dementia. It was the latter two associations that prompted principal author Alcino Silva from UCLA to investigate the relationship between Notch and learning/memory.
First author Rui Costa and colleagues measured learning and memory in adult mice heterozygous for a null mutation in Notch 1. To do this, the authors used the hidden water maze, a test in which mice are placed in a tank of opaque water and must swim in search of a submerged platform on which they can climb to safety. Costa trained the mice in the tank (six times a day) for a number of days, then observed how they reacted when the platform was removed. All mice, conscious of where the platform used to be, spent most of their time swimming in that quadrant of the tank. However, wild-type (WT) mice learned the position of the platform much faster than did Notch mutants. After three days’ training, WT mice spent almost 50 percent of their time searching for the missing platform in the correct quadrant, while mutant mice only spent about 30 percent of their effort there. However, after five days’ training, the mutants had closed the gap and were spending just as much time searching the training quadrant as were normal mice.
Following these experiments, Costa tested the same mice for the ability to find the platform when it was moved to a different quadrant. In this test, Notch mutants learned the new position as readily as wild-type animals, and when the platform was removed they initially spent as much time searching for it in the new quadrant as the normal mice. But after about 48 hours, the Notch mutants had forgotten the new position and started to preferentially search in the old training quadrant.
Together, the experiments indicate that the Notch mutants have trouble learning and remembering where the platform is located. Costa and colleagues also tested the mice for deficits in motor function, visual acuity, and motivation, parameters that could affect the ability to learn and memorize the platform position, but found no statistical difference between wild-type and mutant animals. The authors also probed the Notch pathway and found that animals heterozygous for a null mutation in RBP-J, a downstream target of Notch, showed similar learning and memory defects.
The authors conclude that Notch signaling is involved in learning and memory processes in the adult brain, and suggest that the synaptic dysfunction seen in AD could be caused, in part, by alterations in Notch signaling.—Tom Fagan
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