Makoto Higuchi

Hierarchical order of coexisting pre- and postsynaptic forms of long-term potentiation at synapses in amygdala

Ionotropic glutamate receptor 2 subunit (GluD2) is selectively expressed on the postsynaptic membrane at parallel fiber-Purkinje cell synapses and is required for cerebellar long-term depression (LTD), which has been considered as a critical mechanism for motor learning. Mutant mice deficient in GluD2 show not only impaired LTD but also altered short-term plasticity (paired pulse facilitation), suggesting a possible presynaptic change. Paired pulse facilitation is enhanced in GluD2 knockout mice, suggesting a decreased release probability of synaptic vesicles. We addressed how this occurs. First, we examined the relationship between the external Ca2+ concentration and the paired pulse ratio. The difference in paired pulse ratio between the genotypes became smaller in a low Ca2+ concentration. Blocking Ca2+ channels with Cd2+ also reduced the difference. Theoretical analyses on the Ca2+-dependent release process suggested that the reduced Ca2+ supply to the transmitter-release microzone could explain the experimental results. As Ca2+ dependence of transmitter release process was altered in GluD2 knockout mice, we supposed that Ca2+-dependent long-term plasticity might be also affected. Then, we examined presynaptic long-term potentiation and found that it was suppressed in GluD2 knockout mice. Thus, GluD2 deficiency affected not only postsynaptic LTD but also presynaptic long-term plasticity. Research fund: KAKENHI 23110509 gCOE A06 Kyoto University.

In-vivo PET detection of neurodegenerative pathologies in a transgenic mouse model of tauopathies

Recent studies have implicated Rac1, a Rho family GTPases, participates in Alzheimer’s disease. In this study, we examined the neuroprotective effects of NSC23766, a specific Rac1 inhibitor, on neurotoxicity induced by amyloid betapeptide (Abeta). Abeta42 treatment increased Rac1 activity in primary hippocampal neurons. NSC23766 pretreatment reduced both Rac1 activity and neurotoxicity induced by Abeta. These results indicate that Rac1 activation is involved in Abetainduced neurotoxicity. Activation of glycogen synthase kinase 3beta (GSK3beta) is also reported to be involved in Abeta-induced neurotoxicity; however, the signaling pathway of GSK3beta remains to be elucidated. Interestingly, Abeta42 treatment increased GSK3beta activity and NSC23766 pretreatment reduced this activity. Our results suggest that Rac1, which acts as an upstream factor of GSK3beta, is involved in Abeta-induced neurotoxicity.

Alpha-CaMKII deficiency causes dysregulated behaviours and immature dentate gyrus

P2-j38 Alpha-CaMKII deficiency causes dysregulated behaviours and immature dentate gyrus Nobuyuki Yamasaki1, Motoko Maekawa2, Katsunori Kobayashi3, Yasushi Kajii 4, Jun Maeda5, Miho Soma2, Keizo Takao1, Kouji Kanzaki4, Hidenori Suzuki3, Makoto Higuchi5, Tetsuya Suhara5, Shigeki Yuasa2, Tsuyoshi Miyakawa1 1 Frontier Technology Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2 NIN, NCNP, Tokyo, Japan; 3 Department of Pharmacology, Nippon Medical School, Tokyo, Japan; 4 Mitsubishi Pharma Corporation, Yokohama, Japan; 5 MIC, NIRS, Chiba, Japan