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D. BRUNNER, D.CONNOR, V. ALEXANDROV, V. ISTOMIN, M. DOLGUIKH, P.D.WES, E. SABATH, K. CAVINO, S. OAKESHOTTk, T. HANANIA, D.M.BARTEN, N.X. BARREZUETA, M.K. AHLIJANIAN

The rTg4510 tauopathy mouse model is based on the most common mutation in the tau gene, P301L in exon 10, which causes frontotemporal dementia linked to chromosome 17 (FTDP-17). FTDP17 is an autosomal dominant neurodegenerative disorder which presents with behavioral changes, cognitive impairment, and motor symptoms, and is pathologically characterized by the presence of neurofibrillary tangles and neuronal loss in the forebrain. rTg4510 mice express a transcriptional activator (tTA) that drives Tau(P301L) expression from a second transgene. Our studies had two aims: 1) to assess the phenotype of rTg4510 mice in a comprehensive manner with the view of future drug testing and 2) to assess behavioral differences between controls that contain neither transgene (Dble Neg) and controls that carry only the tTA transgene (tTA Alone). In the PhenoCube system we found no abnormalities in circadian rhythm. Progressive hyperactivity was observed in the rTg4510 mice relative to Dble Neg mice. No major differences in motivation, circadian rhythms, or perseveration were observed, but rTg4510 mice appeared impaired in discrimination learning. In the SmartCube system,Dble Neg mice were statistically different from the tTA Alone and Dble Neg controls at all ages tested. In the NeuroCube system, we observed progressive gait deficits in the rTg4510 mice at all ages tested. In a Procedural T- Maze, rTg4510 mice showed significant deficits during acquisition and reversal. Our analysis suggested early motor and learning deficits in rTg4510. We also saw unexpected phenotypes in the tTA controls compared to Dbl Neg mice. This observation was recapitulated in analysis of gene expression patterns in various brain regions, which revealed differences between tTA and Dbl Neg mice, as well as between Tg4510 mice and both controls. These data emphasize the importance of separately analyzing Dble Neg and tTA Alone control mice when characterizing rTg4510 mice.