神経化学

神経化学企画シンポジウム新たな技術や視点が切り拓くグリア研究の未来

7月7日（金）　8:30-10:30　Room F 2SY②-1 ミクログリア多様性を生み出す胎生期の細胞動態メカニズム The cellular dynamics and mechanisms underlying microglial diversity in the embryonic stage 服部　祐季名古屋大学　大学院医学系研究科　細胞生物学 Yuki Hattori Dept. Anat. Cell. Biol., Grad. Sch. Med., Nagoya Univ. Microglia play multiple roles in the embryonic brain, such as promoting the differentiation of neural progenitors, regulating the maturation of neurons, and vascular formation. Meanwhile, recent advances in single-cell transcriptomic analysis have revealed the diversity of microglia. However, it remains unclear how microglia acquire heterogenous characteristics. We hypothesize two possibilities for this process: (1) the routes through which microglial progenitors reach the brain and the timing of their colonization are different, (2) the surrounding environment of microglia may modulate their property after their arrival. Related to (1), we recently reported that some microglia originate from intraventricular macrophages that infiltrate the brain in the early embryonic stage in mice, based on intravital imaging, cell tracking analysis, and a fate mapping study. In other words, it suggests that microglia have consist of subpopulations that have different origins. Furthermore, our ongoing analyses showed that maternal inflammation alters the properties, distribution, dynamics, and even subpopulation ratios of microglia in fetal brains.In my talk, I will introduce our latest research into the cellular dynamics and molecular mechanisms of microglial colonization into the developing brain, and discuss how microglial behaviors correlate with their diversity and function.		7月7日（金）　8:30-10:30　Room F 2SY②-2 損傷脳におけるグリア細胞とリンパ管のインターラクション Interactions of glial cells with lymphatic vessels in the injured brain 小西　博之, 木山　博資名古屋大学　大学院医学系研究科　機能組織学 Hiroyuki Konishi, Hiroshi Kiyama Dept. Funct. Anat. & Neurosci., Nagoya Univ. Grad. Sch. Med., Nagoya, Japan The brain is known to lack lymphatic vessels. In contrast, lymphatic vessels exist in the dura mater, which is a fibrous membrane covering the brain, to drain cerebrospinal fluid and the wastes contained therein. Because glial cells are apart from dura mater in the healthy condition, direct interactions between glial cells and lymphatic vessels are unlikely. Our recent study using a modified mouse model of middle cerebral artery occlusion revealed that dura mater became thickened after ischemia and adhered with the infarct region of the brain. Visualization of lymphatic vessels demonstrated that dural lymphatic vessels invaded the injured brain via the adhesion bridge to form vessel networks in the injured brain. Activated microglia and astrocytes were located in contact with or very close to newly formed lymphatic vessels, suggesting that glial cells may regulate formation or function of lymphatic vessels in the ischemic brain.

7月7日（金）　8:30-10:30　Room F 2SY②-3 Elucidation of interactive cellular changes between astrocytes and immune cells. 伊藤　美菜子九州大学　生体防御医学研究所 Minako Ito Medical Institute of Bioregulation., Kyushu Univ, Fukuoka, Japan In recent years, the linkage between the nervous system and the immune system has been the focus of much attention. In addition to neurodegenerative diseases such as Alzheimer's disease, the involvement of the immune system has begun to be strongly implicated in the pathogenesis of psychiatric disorders such as autism spectrum disorder (ASD). It is also becoming clear that immune cells are involved in brain development and aging. The interaction between various immune cells and nervous system cells is thought to be important in various events such as pathological conditions, development, and aging.Using a mouse model of cerebral infarction, we have reported on the regulatory mechanisms of inflammation and neurological symptoms by immune responses after cerebral infarction. Here, I will introduce the changes the phenotype of both cells by the interaction between immune cells and astrocytes in the brain during various CNS diseases and in vitro culture system.		7月7日（金）　8:30-10:30　Room F 2SY②-4 アストロサイト由来興奮性分子を介した神経過興奮メカニズム Neuronal hyper-excitability mediated by an excitatory molecule derived from astrocytes 繁冨　英治^1,2, 小泉　修一^1,2 1. 山梨大院医　山梨グリアセンター, 2. 山梨大院医　薬理 Eiji Shigetomi^1,2, Schuichi Koizumi^1,2 1. Yamanashi GLIA Center, Interdiscipl Grad Sch Med, Univ Yamanashi, 2. Dept Neuropharmacol, Interdiscipl Grad Sch Med, Univ Yamanashi Reactive astrocytes display aberrant Ca ²⁺ signals which may be relevant to disease pathogenesis. Among the molecules contributing to aberrant Ca²⁺ signals in reactive astrocytes, P2Y1 receptor (P2Y1R), which is activated by extracellular ATP or ADP, is upregulated in reactive astrocytes in several neurological disorders, such as epilepsy, stroke, and Alzheimer’s disease. To reveal the pathophysiological significance of P2Y1R upregulation in astrocytes, we have used transgenic mice in which astrocytes specifically overexpress P2Y1R using the Tet-Off system (P2Y1OE). P2Y1OE mice were more susceptible to drug-induced seizure and showed more abnormal spikes in EEG recordings, suggesting P2Y1OE triggered neuronal hyper-excitability. To analyze the cellular mechanisms underlying the hyper-excitability in P2Y1OE, we performed Ca²⁺ imaging-based analysis of both neurons and astrocytes and found evidence showing that excitatory synaptic transmission was enhanced in P2Y1OE with induction of aberrant Ca²⁺ signals via P2Y1R in astrocytes. Furthermore, the enhancement of neuronal activities was due to a novel excitatory molecule X derived from astrocytes. Finally, both P2Y1R and the excitatory molecule were upregulated in astrocytes of epilepsy model mice. Overall, our data show a novel mechanism of neuronal hyper-excitability mediated by a molecule derived from astrocytes.

7月7日（金）　8:30-10:30　Room F 2SY②-5 脊髄アストロサイト亜集団による機械刺激に対する行動調節メカニズム Modulation of mechanosensory behavior by a subpopulation of spinal astrocytes 高露　雄太, 津田　誠九州大　院薬　薬理学分野 Yuta Kohro, Makoto Tsuda Dept. Mol. Syst. Parmacol., Grad. Sch. Parm. Sci., Kyushu Univ., Fukuoka, Japan The spinal dorsal horn (SDH) receives somatosensory information from the skin, correctly processes this information via a corresponding neural circuit and then conveys it to the brain. The SDH also receives signals from the brain via descending neurons, which modulates the processing of somatosensory information and behavior. We have recently identified a subpopulation of astrocytes that is defined by expression of the transcription factor Hes5, which is located in superficial laminae in the SDH. In vivo imaging revealed that Hes5⁺ astrocytes increased intracellular Ca²⁺ levels following noxious stimulation via descending noradrenergic (NAergic) signaling from the locus coeruleus (LC), which was crucial for mechanical hypersensitivity. Traditionally, LC-NAergic pathway is considered to be associated with pain inhibition through activating inhibitory interneurons in the SDH. However, we found that chemogenetically stimulated Hes5⁺ astrocytes reduced inhibitory postsynaptic responses, which implies that Hes5⁺ astrocytes stimulated by NA suppress the activity of SDH inhibitory neurons. Thus, Hes5⁺ astrocytes play as non-neuronal gating cells for descending NAergic signaling to modulate mechanosensory behavior.