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P1-1-174 脳室周囲器官のアストロサイトTRPV1による血液情報感知機構 Sensing of blood-derived information by astrocytic TRPV1 in the circumventricular organs of adult mouse brains ○萬成哲也1, 森田晶子1,3, 富永真琴2, 宮田清司1 ○Tetsuya Mannari1, Shoko Morita1,3, Makoto Tominaga2, Seiji Miyata1 京都工芸繊維大院・応用生物1, 岡崎統合バイオ(生理研)・細胞生理2, 奈良県立医大・医・第二解剖3 Dept of Appl Biology, Kyoto Inst of Technol, Kyoto, Japan1, Div of Cell Signaling, Okazaki Inst Integrative Biosci (NIPS), Okazaki, Japan2, Dept of Anat & Neurosci, Nara Med Univ, Nara, Japan3 The brain vasculature has the blood-brain barrier (BBB) that maintains the chemical composition of neuronal milieu for proper functioning of neuronal circuits by preventing free access of blood-derived substances. The sensory circumventricular organs (CVOs) include the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and area postrema (AP) and are able to sense a variety of blood-borne molecules because they lack typical blood-brain barrier (BBB). Though a few signaling pathways are known, it is not known how endogenous ligands for transient receptor potential vanilloid receptor 1 ion channel (TRPV1) are sensed in the CVOs. In the present study, we aimed to examine whether or not astrocytic TRPV1 senses directly blood-borne molecules in the OVLT, SFO, and AP of adult mice. The reverse transcription-polymerase chain reaction and Western analysis revealed the expression of TRPV1 in the CVOs. Confocal microscopic immunohistochemistry further showed that TRPV1 was localized prominently at thick cellular processes of astrocytes rather than fine cellular processes and cell bodies. TRPV1-expressing cellular processes of astrocytes surrounded the vasculature to constitute dense networks. The expression of TRPV1 was also found at neuronal dendrites but not somata in the CVOs. The intravenous administration of an TRPV1 agonist resiniferatoxin (RTX) prominently induced Fos expression at astrocytes in the OVLT, SFO, and AP and neurons in adjacent related nuclei of the median preoptic nuclei (MnPO) and nucleus of the solitary tract (Sol) of wild-type but not TRPV1-knockout mice. The intracerebroventricular infusion of RTX induced Fos expression at both astrocytes and neurons in the CVOs, MnPO, and Sol. Thus, the present study demonstrates that blood	P1-1-175 老化促進モデルマウス（SAMP8）海馬におけるGABA作動性神経伝達機構の発達過程 Development of the GABAergic system in the hippocampus of senescence-accelerated SAMP8 mice ○岩谷可南子1, 澤野恵梨香1, 根岸隆之1, 田代朋子1 ○Kanako Iwatani1, Erika Sawano1, Takayuki Negishi1, Tomoko Tashiro1 青山学院大学　理工学部　化学・生命科学科1 Department of Chemistry and Biological Science, Aoyama Gakuin University, Sagamihara, Kanagawa1 The senescence-accelerated mouse (SAM) is a murine model of accelerated aging which consists of senescence-prone (SAMP) and senescence-resistant (SAMR) strains. Among the SAMP strains classified according to the difference in aging-related pathology, SAMP8 strain shows age-related deficits in learning and memory with little physical impairment, and has been considered as a model of neurodegeneration. However, we found that young SAMP8 mice exhibit hyperactivity, impulsivity, lower anxiety and aggression at 1~5 months (M) before they start showing deficits in learning and memory. Further studies revealed significant attenuation of thyroid hormone (TH) signaling in the hippocampus of SAMP8 compared with that in the normally aging SAMR1, due to down-regulation of deiodinase 2 which is responsible for local conversion of thyroxine (T4) to the transcriptionally active 3, 5, 5'-triidothyronine (T3). Since hypothyroidism has been shown to strongly affect the development of the GABAergic system, we examined the expression of pre- and post-synaptic components of the GABAergic system in the developing SAMP8 hippocampus in the present study. The GABA synthesizing enzymes, GAD67 and GAD65, showed different patterns of expression during development; GAD67 protein increased steadily between 1 and 4w while GAD65 protein showed a rapid and transient increase between 2 to 3w followed by a decrease to the adult level at 4w. Compared with those in the SAMR1 hippocampus, there was a slight decrease in both GAD67 and GAD65 in the SAMP8 hippocampus at 2w, suggesting a small delay in the development of GABA neurons. In addition, 20% decrease in the neuronal K+-Cl- co-transporter, KCC2, was observed in SAMP8 compared with SAMR1 at 2w. Since a rapid induction of KCC2 in the second postnatal week is involved in the switching of GABA action from excitatory to inhibitory, the results indicate that the maturation of GABAergic neurotransmission is also delayed in the SAMP8 hippocampus.
P1-1-176 老化促進モデルマウス(SAMP8)の発達期脳における2型脱ヨード化酵素の減少と行動異常：局所的甲状腺ホルモン低下の原因とその影響 Specific down-regulation of type 2 deiodinase in the SAMP8 hippocampus during development: implications for the cause and effect of subclinical hypothyroidism ○澤野恵梨香1, 根岸隆之1, 田代朋子1 ○Erika Sawano1, Takayuki Negishi1, Tomoko Tashiro1 青山学院大学 理工学部 化学・生命科学科1 Department of Chemistry and Biological Science, School of Science and Engineering, Aoyama Gakuin University, Kanagawa1 The senescence-accelerated mouse prone 8 (SAMP8) strain exhibiting age-associated cognitive deficits with little physical impairment has been considered as a model of neurodegenerative disorders. Recently, however, we found that young SAMP8 mice at 1~5 months (M) display hyperactivity and lower anxiety before they start showing signs of cognitive impairment. Since thyroid disorders have been linked to various psychiatric and neuropsychological disorders, we examined whether brain thyroid hormone (TH) metabolism is involved in the abnormal behavior of young SAMP8 mice using senescence-accelerated mouse resistant 1 (SAMR1) as control. Though plasma levels of thyroxine (T4) and triidothyronine (T3) were comparable at all time points, expression of TH metabolizing enzymes in the hippocampus showed significant differences between the two strains. In the SAMP8 hippocampus, expression of type 2 deiodinase (dio2) which converts T4 into active T3 was down-regulated from the onset of its expression at 3 weeks and throughout development, while that of type 3 deiodinase (dio3) responsible for inactivation of T3 showed a tendency to be up-regulated. In contrast, expression of dio2, TH transporter mct8 and TH receptors became down-regulated in the cerebral cortex of SAMP8 only after 5M. To find the causes for the early down-regulation of dio2 in the SAMP8 hippocampus, global gene expression analysis was performed in the two brain regions of SAMP8 and SAMR1 at 1M. The results suggest the occurrence of basal inflammatory and/or ER stress response in the SAMP8 brain which is elevated in the hippocampus. In addition, though densities of S100b-positive astrocytes were similar and constant in both strains, impairment in astrocyte function was suggested in SAMP8 from alterations in the expression of molecules synthesized and secreted by astrocytes. Since type 2 deiodinase is localized to the ER of astrocytes, its expression may also be affected by functional alterations of astrocytes.

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