Symposia

Symposia Glia-neuron maturation and psychoneurologic diseases／グリアと神経の成熟と精神・神経疾患

3S4-1 Depression and 5HT3 receptor Makoto Kondo Dept Neurosci and Cell Biol, Grad Sch Med, Osaka Univ Depression is a common mental disorder affecting around 350 million people worldwide. Although selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants, a significant proportion of depressed patients do not achieve remission with SSRIs. In this study, we show that a serotonin type 3 receptor (5HT3R) agonist induces antidepressant effects as well as hippocampal neurogenesis independent of fluoxetine (a commonly used SSRI). Notably, our histological analysis reveals that 5HT3R and insulin-like growth factor 1 (IGF1) are expressed in the same neurons in the subgranular zone of the hippocampal dentate gyrus. Furthermore, our in vivo microdialysis analysis shows that 5HT3R regulates hippocampal extracellular IGF1 levels, and we also show that 5HT3R-dependent hippocampal neurogenesis is mediated by increased IGF1 levels. Altogether, our findings suggest a novel 5HT3R-IGF1 mechanism that is distinct from fluoxetine-induced responses and that provides a new therapeutic target for depression, especially bringing significant benefits for SSRI-resistant depressed patients.		3S4-2 Microglia contribute to dendritic spine formation in postnatal mice somatosensory cortex Akiko Miyamoto¹，Hiroaki Wake¹，Ayako Ishikawa^2,3，Hideji Murakoshi⁴，Kei Eto^3,5，Yumiko Yoshimura^2,3，Junichi Nabekura^3,5 ¹Dept System Neurosci, Grad Sch Med, Kobe Univ，²Div Visual Information, Natl Inst Physiol Sci.，³Dept Physiol, Sch Life Sci, SOKENDAI，⁴Supportive Center for Brain Research, Natl Inst Physiol Sci.，⁵Div Homeostatic Develop, Natl Inst Physiol Sci. Microglia, which are the immune cells in the central nervous systems, are one of the glial cells. Because of this immune cell character, microglial functions at injured or pathological condition have been well studied. Over the last decade, it has been revealed that microglia also have some actions for synaptic function and connection during physiological condition using imaging and electrophysiological techniques. For example, microglia selectively contact onto synapses in intact brain and are also involved in circuit refinement via synapse elimination at ischemic penumbra region and developmental period, which may contribute to neural circuit reorganization. Recently, we also found that microglia induce filopodia, which are precursor of spine, during cortical development using in vivo two photon imaging technique. I observed that filopodia was formed at microglial contacted dendritic area. Injection of microglia activation inhibitor decreased cortical spines in density. Microglia specific ablation also decrease spine density. I also examined miniature EPSC frequency and it was significantly reduced in microglia ablated mice. Finally, I investigate whether microglia induced filopodia formation affect to cortical function. To reveal that I investigated the synaptic connection between cortical layers by uncaging photostimulation method. Usually, strength of excitatory synaptic connections from layer 4 to layer 2/3 pyramidal cells are prominent in control mice. However, these are reduced in microglia ablated mice. Taken together, this finding suggests that microglia contributed to neuronal circuit maturation not only via synapse elimination but also via synapse formation during development.

3S4-3 The role of CD38, an Autism-associated molecule, for glial development and demyelination Tsuyoshi Hattori¹，Minoru Kaji¹，Roboon Jureepon¹，Hiroshi Ishii¹，Mika Takarada-Iemata¹，Thoung Manh Le¹，Hiroshi Okamoto^3,4，Yasuhiko Yamamoto³，Haruhiro Higashida²，Osamu Hori¹ ¹Dept Neuroanat, Grad Sch of Med Sci, Kanazawa Univ，²Res. Cent. Child Mental Dev, Kanazawa Univ，³Biochem and Mol Vascular Bio, Grad Sch of Med Sci, Kanazawa Univ，⁴Dept Biochem, Grad Sch Med, Tohoku Univ Glial cells such as astrocytes and oligodendrocytes have emerged as important players in brain function under both physiological and pathological conditions. CD38 is a multifunctional molecule with ADP-ribosyl cyclase activity. While critical roles of CD38 in the adult brain such as oxytocin release and social behavior have been reported, those in the developing brain remain largely unknown. Here we show CD38 is a novel regulator for glial development and activations. First, we demonstrate that deletion of Cd38 leads to impaired development of astrocytes and oligodendrocytes in mice. In situ hybridization analysis revealed that CD38 is expressed predominantly in astrocytes in the developing brain. Analyses of Cd38 knockout (Cd38KO) mice revealed delayed development of astrocytes and oligodendrocytes (OLs) at postnatal stages. In vitro experiments showed that astrocytic CD38 regulates the development of astrocytes in a cell-autonomous manner and the differentiation of OLs in a non-cell-autonomous manner. Further experiments revealed that increased levels of NAD+, caused by CD38 deficiency, are likely to be responsible for the suppression of astrocytic Cx43 expression and OL differentiation. Our data indicate that CD38 is a positive regulator of astrocyte and OL development. Furthermore, to investigate the role of CD38 in pathological condition such as brain inflammation, we made a cuprizone(CPZ)-induced demyelination model of CD38KO mice. We found that CD38 expression was increased in CPZ-administrated WT mice. Interestingly, CPZ-induced demyelination was dramatically attenuated, and microglia and astrocytes were less activated in CD38KO mice. These results suggest that CD38 is also a positive regulator of astrocytes and microglia activation.		3S4-4 VCAM1 regulates oligodendrocyte myelination Junji Yamauchi^1,2，Yuki Miyamoto^1,2 ¹School of Life Sciences, Tokyo University of Pharmacy and Life Sciences，²Department of Pharmacology, NICHD Oligodendrocytes differentiate to wrap their plasma membranes around axons, forming the myelin sheath. A neuronal cue is one of the regulator elements controlling this process. Here, we demonstrate that VCAM1, which plays a key role throughout the immune system, is also expressed in oligodendrocytes, where it regulates the initiation of myelination. VCAM1 knockout mice exhibit reduced myelin thickness. Decreased myelin thickness is also observed in mutant mice of α4 integrin, which is a neuronal VCAM1 ligand. Therefore, VCAM1 contributes to the initiation of myelination, demonstrating that an intercellular molecule whose primary role is in the immune system can also play an unexpected role in the CNS.

3S4-5 Molecular mechanisms of the onset of neuropsychiatric disorders by the changes in glial functions Shingo Miyata¹，Shoko Shimizu¹，Yugo Ishino¹，Masaya Tohyama^1,2 ¹Div. of Mol. Brain Sci., Res. Ins. of Trad. Asian Med., Kindai Univ.，²Osaka Pref. Hosp. Org. The major psychiatric disorders, such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained up-regulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendorocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought be related to depressive-like symptoms. Thus, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD.