Using techniques and equipment modified from his pioneering studies of place cells in rats, O'Keefe, along with first author Francesca Cacucci and colleagues Ming Yi and Thomas Wills of UCL and Paul Chapman of the GlaxoSmithKline Centre for Cognitive and Neurodegenerative Disorders in Singapore, implanted microelectrodes in the hippocampal pyramidal cells of 42 animals. The investigators divided the mice into four groups: young and old controls, and young and old Tg2576 mice. The researchers then tested the spatial memory of each group over 12 days of trials while simultaneously recording from the behaving mice. Cacucci and colleagues used a T-maze rather than the traditional water maze because, as O'Keefe noted, live wires and water don't mix. The place cells of the aged Tg2576 mice showed functional differences that are known to coarsen the resolution of spatial mapping: the field size of the cells was larger, for example, and the amount of spatial information they processed was lower than in the other groups. Those differences correlated with deficits in the animals' spatial memory.

Because such physiological changes may actually occur before overt behavioral deficits, O'Keefe says, space-cell malfunction could become an early indicator of disease onset. "We suspect we'll begin to see signs of changes in the function of the cells before we see changes in behavioral tasks." Deficits in spatial memory are among the early signs of Alzheimer disease (see, e.g., deIpolyi et al., 2007).

O'Keefe and his colleagues also found that hippocampal plaque burden correlated with the level of place cell degradation. This observation taps into an ongoing debate in the field about which forms of Aβ peptide (and tau protein, for that matter) do the most damage to neuronal function during the pathogenesis of AD. Besides having developed the Tg2576 mouse, Karen Hsiao Ashe of the University of Minnesota Medical School in Minneapolis is a leading investigator on that issue. Ashe commented by e-mail that more than two time points would be needed to implicate amyloid plaques in causing the place cell deficits (see extended comment below). O'Keefe is quick to agree. He is planning further studies with more time points, but "it didn't make any sense to do intermediate time points until we knew there were differences in the first and last ones," O'Keefe says. In these further experiments, O'Keefe plans to collaborate with John Hardy, who last year moved from the U.S. National Institutes of Health back to his native U.K., and UCL.

Hongxin Dong of Washington University School of Medicine in St. Louis, Missouri, told this reporter that the place cell work opens the door to several other avenues of study. "It would be interesting to…inspect the morphology of the individual place cells as well as their location in reference to nearby plaques," she noted in an e-mail with colleague Nicole Hicklin (see comment below). Dong has carefully analyzed the relationship between synaptic loss and amyloid deposits in the Tg2576 mice (see Dong et al., 2007).

Another independent group that studies transgenic mouse models of AD is Lennart Mucke's at the Gladstone Institute of Neurological Diseases at the University of California, San Francisco. Erik Roberson and Jorge Palop in that group said the paper closes a gap between behavioral studies showing learning and memory deficits in aged Tg2576 mice and in-vitro cellular studies showing deficits in synaptic plasticity, particularly long-term potentiation, as demonstrated by the landmark paper Chapman et al., 1999. "This observation interposes between those two previous findings quite nicely," Roberson said. Palop added that the place cell deficits may be more relevant to disease symptoms than the LTP deficits observed at the cellular level.

But Palop cautioned that the place cell recording technique is time-consuming and elaborate. "It's going to be restricted to a subset of labs that have the capacity to do this electrophysiological tracking," Roberson agreed. At present, just a handful of other investigators are equipped to do place cell recordings in living, freely moving mice: Eric Kandel's lab at Columbia University, New York, for example, and Susumu Tonegawa's and Matt Wilson's at MIT. To his knowledge, neither group is looking at AD-model mice, O'Keefe said. He hopes to generate interest in AD among other place cell researchers, so that place cell recordings may eventually help to identify the pathology of AD and serve as a platform for testing therapeutic interventions.—Karen Wright.

Karen Wright is a freelance writer in New Hampshire.

Reference:
Cacucci F, Yi M, Wills TJ, Chapman P, O'Keefe J. Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model. Proc Natl Acad Sci U S A. 2008 May 27; Abstract