Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice

Fumiko Arima-Yoshida, Matthieu Raveau, Atsushi Shimohata, Kenji Amano, Akihiro Fukushima, Masashi Watanave, Shizuka Kobayashi, Satoko Hattori, Masaya Usui, Haruhiko Sago, Nobuko Mataga, Tsuyoshi Miyakawa, Kazuhiro Yamakawa, Toshiya Manabe

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Abstract

Down syndrome is a complex genetic disorder caused by the presence of three copies of the chromosome 21 in humans. The most common models, carrying extra-copies of overlapping fragments of mouse chromosome 16 that is syntenic to human chromosome 21, are Ts2Cje, Ts1Cje and Ts1Rhr mice. In electrophysiological analyses using hippocampal slices, we found that the later phase of the depolarization during tetanic stimulation, which was regulated by GABAB receptors, was significantly smaller in Ts1Cje and Ts2Cje mice than that in WT controls but not in Ts1Rhr mice. Furthermore, isolated GABAB receptor-mediated inhibitory synaptic responses were larger in Ts1Cje mice. To our knowledge, this is the first report that directly shows the enhancement of GABAB receptor-mediated synaptic currents in Ts1Cje mice. These results suggest that GABAB receptor-mediated synaptic inhibition was enhanced in Ts1Cje and Ts2Cje mice but not in Ts1Rhr mice. The Cbr1 gene, which is present in three copies in Ts1Cje and Ts2Cje but not in Ts1Rhr, encodes carbonyl reductase that may facilitate GABAB-receptor activity through a reduction of prostaglandin E2 (PGE2). Interestingly, we found that a reduction of PGE2 and an memory impairment in Ts1Cje mice were alleviated when only Cbr1 was set back to two copies (Ts1Cje;Cbr1+/+/−). However, the GABAB receptor-dependent enhancement of synaptic inhibition in Ts1Cje was unaltered in Ts1Cje;Cbr1+/+/− mice. These results indicate that Cbr1 is one of the genes responsible for DS cognitive impairments and the gene(s) other than Cbr1, which is included in Ts1Cje but not in Ts1Rhr, is responsible for the GABAB receptor-dependent over-inhibition.

Original languageEnglish
Article number14187
JournalScientific reports
Volume10
Issue number1
DOIs
Publication statusPublished - 01-12-2020

All Science Journal Classification (ASJC) codes

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    Arima-Yoshida, F., Raveau, M., Shimohata, A., Amano, K., Fukushima, A., Watanave, M., Kobayashi, S., Hattori, S., Usui, M., Sago, H., Mataga, N., Miyakawa, T., Yamakawa, K., & Manabe, T. (2020). Impairment of spatial memory accuracy improved by Cbr1 copy number resumption and GABAB receptor-dependent enhancement of synaptic inhibition in Down syndrome model mice. Scientific reports, 10(1), [14187]. https://doi.org/10.1038/s41598-020-71085-9