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Magnusson Lab: Research
 

Aging and Calorie Restriction

3 month old

27 month old ad libitum-fed

26 month old calorie restricted

  

NMDA Receptor Binding: There is a significant decrease in the density of binding of transmitter to NMDA receptors between young and old mice. Caloric restriction is an intervention into the aging process that delays many of the effects of aging, including memory declines. There is a slight sparing of NMDA receptor binding in aged mice that are calorie restricted. NMDA receptor density correlates with spatial memory abilities during aging.
In situ hybridization for the epsilon2 subunit mRNA: The epsilon2 subunit of the NMDA receptor (NR2B in non-mouse species) shows the greatest declines in mRNA density during aging of all the NMDA subunits examined. Caloric restriction did not significantly delay the decline in the mRNA expression of the epsilon2 subunit. This suggests that caloric restriction does not prevent or slow all of the changes that are associated with aging.
 
In situ hybridization for the zeta1 subunit mRNA: The zeta1 subunit shows mild declines in mRNA expression during aging. Caloric restriction appears to up-regulate the expression of mRNA for the zeta1 subunit during aging, suggesting that it may stimulate some compensatory mechanisms middle age.

For more details about NMDA receptor binding and mRNA changes during aging in mice, dogs, and primates, please see the following:

Magnusson, K.R. (2000) Declines in mRNA expression of different subunits may account for differential effects of aging on agonist and antagonist binding to the NMDA receptor. J. Neurosci. 20:1666-1674.

Magnusson, K.R., C. Rinehart, A. Wagner and C. Dunlop (2000) Changes in anesthetic sensitivity and glutamate receptors in the aging canine brain. J. Gerontol. Biol. Sci. 55A: B448-B454.

Magnusson, K.R. (2001) Influence of diet restriction on NMDA receptor subunits and learning during aging. Neurobiol. Aging 22: 613-627.

Bai, L., P.R. Hof, D.G. Standaert, Y. Xing, S.E. Nelson, A.B. Young, and K.R. Magnusson (2003) Changes in the expression of the NR2B subunit during aging in macaque monkeys. Neurobiol. Aging (in Press).
 
Daniel Kronemann
Example of film obtained with receptor binding or in situ hybridization.  Representative brain sections from each age and diet group are present on each film.  Multiple sections from each animal are analyzed.  The film is scanned and analyzed by computer.  Daniel is analyzing the density of binding within specific brain regions on a single section.

 
Future directions
We have found relationships between NMDA receptor expression in the prefrontal cortex and both short-term and long-term memory abilities.  We are trying to learn more about the role of NMDA receptors in the prefrontal cortex in spatial memory in normal young adult mice.  We are also trying to reduce the expression or function of the epsilon2 subunit in young mice and seeing how that influences spatial memory.  This serves to remove all the other variables associated with aging and will allow us to determine how important the NMDA receptor changes are to the aged mice.
 

Aging and Protein Expression of NMDA Receptor Subunits

 
Rebecca Hammersmark Xue Zhao
Rebecca is preparing brain tissue for Western blotting.  We perform semi-quantitative Western blots by loading 5-6 wells on each gel with different microgram amounts of protein, as shown on the right side of the film above.  The film is examined by Xue, scanned into the computer, and the bands are analyzed.  A standard curve is obtained with the caudal cortex bands and is used to obtain semi-quantitative measurements of the samples from different ages of mice (on the right side of the film).

 

Future directions
We are working on examining the protein expression of the NMDA receptor subunits in different parts of the neurons from different ages of mice. This will include subunits being produced, subunits that are involved in neurotransmission and subunits that are “on deck” or being removed from the synapse. This will help us to determine what’s going wrong with the expression of the NMDA receptor in aged mice. We are also adjusting our Western blotting protocols to make use of the new Li-Cor Odyssey Imaging System.
 

Spatial Memory Testing
Sarah Hoffman Morris water maze Jason Dutton

The Morris water maze is used to test spatial memory ability in rodents.  A round water tank is filled with water that is colored white with non-toxic paint.  Cues are placed on the walls and the wall of the tank.  A platform is hidden below the surface of the water.  The mouse uses the cues to make a spatial map of the room.  An animal that is good at making and retrieving this map will get better and better at finding the hidden platform with repeated swim trials.  Sarah and Jason worked on a short-term memory protocol for the water maze this summer.
 

Photos of the computer monitor showing the behavioral tracking system.  The left image shows the location of the platform (small circle).  The middle image shows the path of a mouse that is early in the learning process.  The image on the right shows the path of a mouse that has learned the location of the hidden platform well.

Future directions
We will continue to use the Morris water maze to characterize the learning abilities of different ages of mice prior to assessing NMDA receptor expression.  We will also use the spatial memory tasks to better understand the role of the NMDA receptors in prefrontal cortex in spatial learning and memory.
 

To read more about our experiments with long-term (reference) and short-term (working) memory, please see the following:

Magnusson, K.R. (2001) Influence of diet restriction on NMDA receptor subunits and learning during aging. Neurobiol. Aging 22: 613-627.

Magnusson, K.R., B. Scruggs, J. Aniya, K.C. Wright, T. Ontl, Y.Xing, L. Bai (2003) Age-related deficits in mice performing working memory tasks in a water maze. Behav. Neurosci. 117:485-495.

 
 

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Magnusson Lab
Department of Biological Sciences
Room 247, Gibb Hall
University of Idaho
P.O. Box 443051
Moscow, ID 83844-3051
Lab Phone: (208) 885-5754
Email: kmagnuss@uidaho.edu

Updated January 2004
Website enhancements were supported by the NSF-Idaho EPSCoR program and by the National Science Foundation under award number EPS-0132626.