Symposia

Symposia Microglia-endocrine interaction in health and disease／ミクログリアー内分泌連関

2S4-1 Effects of glucocorticoids on microglial cells in health and disease Junya Tanaka，Mohammed E Choudhury，Hajime Yano Ehime Univ, Grad Sch Med, Dept Molecul Cell Physiol Microglial cells rapidly become activated in response to a variety of brain pathology, and it is well-known that glucocorticoids suppress their proinflammatory activation. However, glucocorticoid actions are not limited to the anti-inflammation. In a rat stroke model prepared by tMCAO, activated microglia with enlarged somata were located in peri-ischemic lesion. Treadmill exercise as rehabilitation ameliorated ischemia-induced brain edema by increasing plasma corticosterone levels. Microglia expressed Na⁺/H⁺ exchanger 1 (NHE1), and corticosterone suppressed the NHE1 expression in cultured microglia. A NHE1 inhibitor EIPA caused shrinkage of microglial somata. Thus, plasma glucocorticoids might play as a cell size determinant. A synthetic glucocorticoid dexamethasone suppresses microglial phagocytosis in vitro. This action may be correlated with the phagocytic elimination of synapses by microglia in the normal and pathologic brains. In a 6-OHDA-induced rat Parkinsonism model, microglial activation was observed in substantia nigra pars reticulata where damaged neurons were not present. The activated microglia phagocytosed glutamatergic synapses from the subthalamic nuclei that became hyperactive due to the parkinsonism. Dexamethasone inhibited the phagocytic elimination of synapses, causing deterioration of the motor functions. Even in the normal mature rat cerebral cortex, microglial cells phagocytosed synapses rather actively during daytime or sleeping periods for rats. The phagocytic elimination of synapses may be correlated to sleep/wake cycle. Suppression of the synaptic elimination by dexamethasone decreased non-REM sleep. These observations suggest that glucocorticoids may be responsible for various physiologic and pathologic microglial actions of microglia.		2S4-2 Effects of thyroid hormones on microglial function and neuron-glia interaction Mami Noda¹，Yusaku Yoshioka¹，Yosuke Kitahara²，Akinori Nishi² ¹Lab Pathophysiol, Grad Sch Pharm Sci, Kyushu Univ，²Dept Pharmacol, Kurume Univ Sch Med Thyroid hormones (THs) are essential for the development and function of the central nervous system (CNS). In the CNS, circulating thyroxine (T4) crosses blood-brain barrier via specific transporters and is taken up to astrocytes. T4 becomes L-tri-iodothyronine (3, 3’, 5–triiodothyronine; T3), an active form of TH, by type 2 de-iodinase (D2), and T3 is released to the brain parenchyma from astrocytes (glioendocrine system). In adult CNS, both hypo- and hyper-thyroidism, the prevalence in female being >10 times higher than that in male, may affect psychological condition and potentially increase the risk of cognitive impairment and neurodegeneration including Alzheimer’s disease. We have reported the non-genomic effects of T3 on microglial functions and its signaling and the sex- and age-dependent effects of THs on glial morphology in the mouse brains of hyperthyroidism. Behavioral changes also showed sex-dependence. The significant effect of THs on spine density of granule cells in the hippocampal dentate gyrus in male hyperthyroidism was detected as well. These results may help to understand physiological and/or pathophysiological functions of THs in the CNS and how hyperthyroidism affects behavioral and psychological conditions.

2S4-3 Pre-exposure to psychosocial stress induces polyI:C-induced allodynia and depressive-like behavior Takakazu Oka^1,2，Takeharu Chijiwa¹，Battuvshin Lkhagvasuren¹，Nobuyuki Sudo¹ ¹Dept of Psychosomatic Med, Grad Sch Med　Sci, Kyushu Univ，²Dept Psychosomatic Med, International Univ Health and Welfare hospital Background: When animals suffer from viral infections, they develop sickness response such as fever, allodynia and depressive-like behavior. Recent studies suggest that psychological stress can modulate the sickness response. However, it remains uncertain whether acute and chronic/repeated stress has the same effect. Methods: To address this question, we compared changes in polyI:C (3 mg/kg, ip)-induced fever, mechanical allodynia and depressive-like behavior in rats that had been pre-exposed to single and repeated (1-hr daily, five days) social defeat stress.Results: PolyI:C-induced fever was attenuated by the pretreatment with either single or repeated social defeat stress. In contrast, only the repeated stress group showed late-onset and prolonged mechanical allodynia lasting for 35 days after injection in the von Frey test and prolonged immobility time in the forced swim test 9 days post-injection. To assess the involvement of glucocorticoids and microglia in these phenomena, we investigated the effect of pretreatment with RU486 (50 mg/kg ip), a glucocorticoid receptor antagonist, and minocycline (50 mg/kg ip), an inhibitor of microglial activation, on polyI:C-induced allodynia and depressive-like behavior. Pretreatment with either drug inhibited both the delayed allodynia and depressive-like behavior. Conclusions: This study demonstrates that repeated, but not single, social defeat stress followed by systemic polyI:C administration induced prolonged allodynia and late-onset depressive-like behavior in rats. Stress-induced corticosterone and microglial activation may play a pivotal role in these phenomena.		2S4-4 An OXTR-gene deficient ASD model mice showed activated microglial cells and multiple impairments Katsuhiko Nishimori，Shinji Miyazaki，Yuichi Hiraoka ，Shizu Hidema Dept Mol Biol. Grad Sch Agriculture, Tohoku Univ Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong relation to multiple genetic components, and also partly suspected with abnormal environment during fetal development. ASD is characterized by impaired communication, difficulty in companionship, repetitive behaviors and restricted interests.Recent genetic studies of ASD gave us tremendous progress and outcome, and also clinical trials have shown amelioration of ASD symptoms by intranasal administration of oxytocin. On the other hand, plural candidate genes with potential to cause ASD were identified, and the genetic studies might provide a reliable basis for future translational study for better diagnoses, intervention and curing ASD. However, it is more difficult to clarify the mechanism in the brain, with which suspected genes lead carriers to ASD. Oxytocin receptor gene (Oxtr) is one of those causatively candidate genes, and several cohort studies demonstrated significant association between the polymorphisms in the Oxtr gene and ASD patients.We analyzed brain prepared from Oxtr gene deficient mice, found deficient pruning of synapses by microglial cells, and here we propose the activation of microglial cells as one of potential mechanisms to cause ASD.We found abnormal activation of microglial cells and a reduction of postsynaptic density protein PSD95 expression in the Oxtr-deficient brain.On the other hand, in Oxtr KO mice also showed multiple impaired aspects in neural circuitry, and characteristics of c-fos activation in several nuclei when mice were socially stimulated.Relation between activated microglial cells and impaired signal/circuitry in Oxtr KO mice will be discussed.