京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22358号 / 医博第4599号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 岩田 想, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Learning and memory are important processes that occur in the brain. The brain is comprised of neurons that make connections with each other known as synapses. Synaptic plasticity is widely believed to be the physiologic mechanism by which learning and memory occur. Synapses can either be strengthened through a process known as long-term potentiation (LTP) or weakened through long-term depression (LTD). The area of the brain that is most studied for its role in learning and memory is the hippocampus, which has been shown to be involved in memory consolidation. The detection of endocannabinoids and their receptors has opened a whole new field of study in regards to synaptic plasticity. Cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1) are among the commonly studied endocannabinoid receptors found in the central nervous system. In the brain, these receptors' natural ligands, anandamide and 2-arachidonylglycerol (2-AG), are found in abundance. Yet not all forms of observed plasticity are accounted for by just these two receptors, so studies into other G-protein coupled receptors (GPCRs) continues. One GPCR, GPR55 is found in many regions of the brain, as well as lysophosphatidylinositol (LPI), its specific ligand. Here we have researched the role of GPR55 in modulating synaptic plasticity in the hippocampus. Using quantitative reverse transcription PCR and immunohistochemistry, we have found GPR55 to be expressed in the hippocampus with highest expression in pyramidal cells, the main excitatory neurons in the hippocampus. Using field and whole cell electrophysiology, we have investigated its effects on synaptic plasticity, discovering that activation of GPR55 by LPI significantly enhances LTP. In memory behavioral assays there are no significant differences between GPR55 KO mice and wild type littermates, indicating that it may not be involved in endogenous memory processes. However, our electrophysiology data makes GPR55 a potential target for treating memory disorders such as dementia. We have also investigated GPR18 and GPR119 for their potential roles in synaptic plasticity. First, we confirmed their expression in the hippocampus and then investigated the effects of their agonists on plasticity. Another receptor, TRPV1 has been studied to alter plasticity. However, the study of how protein translation and RNA transcription involvement in TRPV1 plasticity in mammals has not been investigated. While translation and transcription are known to be important in many forms of LTP, it is unknown whether these processes are important for TRPV1-induced LTD. We are investigating their necessity via whole cell patching and using translation and transcription inhibitors Anisomycin and Actinomycin D, both previously used in slice electrophysiology.