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The Journal of Neuroscience, October 7, 2009, 29(40):12636-12640; doi:10.1523/JNEUROSCI.1948-09.2009

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Neurobiology of Disease
A Reporter of Local Dendritic Translocation Shows Plaque- Related Loss of Neural System Function in APP-Transgenic Mice

Melanie Meyer-Luehmann,^1,2,3 Matthew Mielke,¹ Tara L. Spires-Jones,¹ Will Stoothoff,¹ Phill Jones,¹ Brian J. Bacskai,¹ and Bradley T. Hyman¹

¹MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Alzheimer's Disease Research Laboratory, Charlestown, Massachusetts 02129, and ²Deutsches Zentrum für Neurodegenerative Erkrankungen and ³Adolf-Butenandt-Institute for Biochemistry, Ludwig Maximilians-University, Munich 80336, Germany

Correspondence should be addressed to Dr. Bradley T. Hyman, Massachusetts General Hospital, Department of Neurology, Alzheimer's Disease Research Laboratory, 114 16th Street, Room 2009, Charlestown, MA 02129. Email: bhyman{at}partners.org

Although neuronal communication is thought to be summated within local dendritic segments, no technique is currently available to monitor activity in vivo at this level of resolution. To overcome this challenge, we developed an optical reporter of neuronal activity using the coding sequence of Venus, flanked by short stretches of the 5'- and 3'-untranslated regions from calcium/calmodulin-dependent kinase II (CAMKII). This reporter takes advantage of the fact that CAMKII mRNA is transported to the dendrite and locally translated in an activity-dependent manner. Using adeno-associated virus, we used this reporter to study neuronal activity in adult mice. Exposure of the mice to an enriched environment led to enhancement of Venus expression in dendritic segments of somatosensory cortex, demonstrating in vivo that dendritic mRNA translocation and local translation occur in response to physiologically relevant stimuli. We then used this system to examine the impact of Alzheimer-related local amyloid-β deposits on neural system function to test the hypothesis that plaques are toxic. In APPswe/PS1dE9 (APP/PS1) mice, neurons close to plaques, and dendritic segments close to plaques, both showed diminished fluorescent intensity and therefore neuronal activity. In contrast to wild-type mice, fluorescent intensity in neurons near plaques in transgenic mice did not increase after environmental enrichment. These data indicate that neuronal activity in dendritic segments and neurons in the vicinity of a plaque is decreased compared with wild-type mice, supporting the idea that plaques are a focal lesion leading to impaired neural system function.

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Received April 24, 2009; revised June 26, 2009; accepted July 7, 2009.

Correspondence should be addressed to Dr. Bradley T. Hyman, Massachusetts General Hospital, Department of Neurology, Alzheimer's Disease Research Laboratory, 114 16th Street, Room 2009, Charlestown, MA 02129. Email: bhyman{at}partners.org

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