Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice
Introduction
Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) are common forms of age-related dementing diseases. Whereas AD is characterized by extracellular β-amyloid-containing plaques and intracellular neurofibrillary tangles (NFT), in neurodegenerative diseases such as FTDP-17, NFT form in the absence of amyloid plaques Gotz, 2001, Lee et al., 2001. In cells affected in these tauopathies, the microtubule-associated protein tau is abnormally phosphorylated and relocalized from axonal to somatodendritic compartments where it accumulates in pretangle, filamentous aggregates that eventually assemble into NFT Buee et al., 2000, Goedert et al., 1995. The discovery of mutations in the tau gene in FTDP-17 established that dysfunction of tau alone can cause neurodegeneration and lead to dementia Hutton et al., 1998, Poorkaj et al., 1998, Spillantini et al., 1998.
Expression of FTDP-17 mutant tau in transgenic mice caused NFT formation both in neurons Allen et al., 2002, Gotz et al., 2001a, Lewis et al., 2000, Tanemura et al., 2001, Tatebayashi et al., 2002 and in glial cells Gotz et al., 2001b, Higuchi et al., 2002, Lin et al., 2003. Whereas extensive behavioral studies have been performed in β-amyloid-forming APP transgenic mice Chapman et al., 1999, Chen et al., 2000, Dodart et al., 1999, Hsiao et al., 1996, Janus et al., 2000, Morgan et al., 2000, Routtenberg et al., 1997, less information is available for tau mutant mice Tanemura et al., 2002, Tatebayashi et al., 2002. We investigated our P301L (FTDP-17) mutant mice in several amygdala-dependent tasks because tau aggregates mainly formed in the amygdala (Gotz et al., 2001c). This brain area is involved in mediating effects of emotion and stress on learning and memory as determined in fear conditioning and conditioned taste aversion (CTA) tests LeDoux, 2000, Welzl et al., 2001. It plays a role in modulating consolidation processes which involve other brain areas (McGaugh et al., 2002). To correlate behavior with tau expression, we determined the distribution of P301L tau in more detail with special emphasis on brain areas shown to be involved in CTA.
We found that the P301L mice showed increased exploratory behavior but normal anxiety levels and no impairment in fear conditioning. CTA is a well-established learning and memory paradigm in which subjects learn to associate a novel taste with nausea and, as a consequence, avoid consumption of this specific taste at the next presentation. Acquisition and consolidation of CTA memory were not significantly affected by the transgene. However, transgenic mice extinguished the CTA more rapidly than wild-type mice. Together, our data show that tau aggregation, as found in particular in the basolateral and basomedial nucleus of the amygdala, has functional consequences for specific forms of learning and memory.
Section snippets
Animals
The transgenic mice used in this study express the human pathogenic mutation P301L of tau together with the longest human brain tau isoform (htau40) under control of the neuron-specific mThy1.2 promoter. Pronuclear injections were done into C57Bl/6 × DBA/2 F2 oocytes to obtain founder animals that were back-crossed with C57Bl/6 mice to establish transgenic lines (Gotz et al., 2001a). Line pR5-183 expressed mutant human tau in many brain areas; however, NFT formation was mainly confined to the
Expression pattern of P301L tau
To determine the expression pattern of human P301L tau in more detail, with special emphasis on brain areas involved in the CTA task, we analyzed frontal sections of four P301L tau expressing mice by immunohistochemistry using the human tau-specific antibody HT7 and the phosphorylation-dependant anti-tau antibody CP13 (Fig. 1). We found expression of human tau in the motor, somatosensory and insular cortex (IC) and in the claustrum at position AP +1.1 mm. At AP −0.82, tau was present in
Discussion
Our immunohistochemical and behavioral analysis of P301L tau transgenic mice revealed a widespread aggregation of tau in the forebrain that is accompanied by selective changes in behavior. Behavioral changes include a small increase in exploratory behavior and an accelerated extinction of an aversion against a taste that has been previously paired with nausea. No changes, with respect to wild-types, were found in locomotor activity, fear conditioning, taste neophobia, and unconditioned natural
Acknowledgements
The authors thank Eva Moritz for help with immunohistochemistry, Dr. David Wolfer for data analysis, and Dr. Peter Davies for antibody CP13. This research was supported in parts by grants from the SNF, the ZNZ (Neuroscience Center Zurich), the Hartmann Müller Fund, the Olga Mayenfisch Foundation and by the NCCR “Neuronal plasticity and repair”.
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