Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model
The Journal of Neuroscience, April 22, 2020 • 40(17):3491–3501 • 3491 Neurobiology of Disease Selective Disruption of Inhibitory Synapses Leading to Neuronal Hyperexcitability at an Early Stage of Tau Pathogenesis in a Mouse Model Masafumi Shimojo,1 Hiroyuki Takuwa,1 Yuhei Takado,1 Masaki Tokunaga,1 Satoshi Tsukamoto,2 Keiichiro Minatohara,1 Maiko Ono,1 Chie Seki,1 Jun Maeda,1 Takuya Urushihata,1 Takeharu Minamihisamatsu,1 Ichio Aoki,3 Kazunori Kawamura,4 Ming-Rong Zhang,4 Tetsuya Suhara,1 Naruhiko Sahara,1 and Makoto Higuchi1 1Department of Functional Brain Imaging, 2Laboratory Animal and Genome Sciences Section, 3Department of Molecular Imaging and Theranostics, and 4Department of Radiopharmaceuticals Development, National Institutes for Quantum and Radiological Science and Technology, Chiba, 263-8555, Japan Synaptic dysfunction provoking dysregulated cortical neural circuits is currently hypothesized as a key pathophysiological pro- cess underlying clinical manifestations in Alzheimer’s disease and related neurodegenerative tauopathies. Here, we conducted PET along with postmortem assays to investigate time course changes of excitatory and inhibitory synaptic constituents in an rTg4510 mouse model of tauopathy, which develops tau pathologies leading to noticeable brain atrophy at 5-6 months of age. Both male and female mice were analyzed in this study. We observed that radiosignals derived from [11C]flumazenil, a tracer for benzodiazepine receptor, in rTg4510 mice were significantly lower than the levels in nontransgenic littermates at 2- 3 months of age. In contrast, retentions of (E)-[11C]ABP688, a tracer for mGluR5, were unaltered relative to controls at 2 months of age but then gradually declined with aging in parallel with progressive brain atrophy.
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