Memory trace interference impairs recall in a mouse model of Alzheimer’s disease

• Published in: Nature neuroscience Vol. 23; no. 8; pp. 952 - 958
• Main Authors: Poll, Stefanie, Mittag, Manuel, Musacchio, Fabrizio, Justus, Lena C., Giovannetti, Eleonora Ambrad, Steffen, Julia, Wagner, Jens, Zohren, Lioba, Schoch, Susanne, Schmidt, Boris, Jackson, Walker S., Ehninger, Dan, Fuhrmann, Martin
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2020; Nature Publishing Group
• Subjects: 13/44; 14/19; 14/35; 14/69; 38/22; 42/44; 631/378/1595/1554; 631/378/1595/2636; 631/378/1689/1283; 64/110; 64/60; 82/51; Activation; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Complications and side effects; Development and progression; Disease Models, Animal; Female; Health aspects; Hippocampus; Hippocampus (Brain); Hippocampus - physiology; Interference; Male; Memory tasks; Memory, Disorders of; Mental Recall - physiology; Mental task performance; Mice; Mice, Transgenic; Mimicry; Neurobiology; Neurodegenerative diseases; Neurons - physiology; Neurosciences; Optogenetics; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Psychological aspects; Recall; Transgenic mice; Germany; Alzheimer's disease; Hippocampus; Fear conditioning
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/s41593-020-0652-4

In Alzheimer’s disease (AD), hippocampus-dependent memories underlie an extensive decline. The neuronal ensemble encoding a memory, termed engram, is partially recapitulated during memory recall. Artificial activation of an engram can restore memory in a mouse model of early AD, but its fate and the factors that render the engram nonfunctional are yet to be revealed. Here, we used repeated two-photon in vivo imaging to analyze fosGFP transgenic mice (which express enhanced GFP under the Fos promoter) performing a hippocampus-dependent memory task. We found that partial reactivation of the CA1 engram during recall is preserved under AD-like conditions. However, we identified a novelty-like ensemble that interfered with the engram and thus compromised recall. Mimicking a novelty-like ensemble in healthy mice was sufficient to affect memory recall. In turn, reducing the novelty-like signal rescued the recall impairment under AD-like conditions. These findings suggest a novel mechanistic process that contributes to the deterioration of memories in AD. Mice with AD-like pathology and memory impairments surprisingly have memory engrams in their hippocampus. However, interference with novelty-like cells prevents proper recall, erroneously letting mice perceive a previously learned context as novel.