檀上 洋右さん、鈴木 秀明さん

医学部医学科 2014年、2018年入学

2021年7月28日-31日 神戸コンベンションセンター


薬理学教室 檀上洋右



Glial cells play a pivotal role in the modulation of synaptic connections and healthy development of brain networks. They control the excitatory / inhibitory synaptic balance and assemble neural circuity by forming new synapses through secreting synaptogenic molecules or neurotrophic factors, or by elimination through phagocytosis. We have recently revealed that astrocytes form excitatory synapses in the adult injured brain through mGluR5 signaling. However, astrocytic mGluR5 is, in health brain, expressed in the limited time-window of the postnatal developmental stage. All these findings suggest that astrocytic mGluR5 has an important role in assembly of synaptic connections in the critical period. Thus, we surveyed how astrocytic mGluR5 destines the subsequent synapse scaling using astrocyte-specific mGluR5 KO mice (cKO). Astrocytes in cKO were slightly reactive in the critical period. Unexpectedly, the number of excitatory synapses did not decrease much, instead, the number of inhibitory synapses decreased significantly in cKO throughout ages. This decrease was due to phagocytosis by microglia. In fact, microglia frequently engulfed inhibitory synaptic elements in the critical period in cKO. Astrocytic mGluR5 expression were transient event in the critical period, however, behavioral dysfunction was observed in adult cKO mice. Hence, we conclude that astrocytes organize inhibitory network in the critical period by somehow modulating microglial phagocytic activity, for which mGluR5 has an inhibitory role. It should be noted that although mGluR5 is only transiently expressed in astrocytes in the critical period, its function greatly affects the inhibitory neuronal networks throughout life.





薬理学教室 鈴木秀明






Emerging evidence suggests that glial cells such as astrocytes and microglia regulate synapses through bidirectional communication. Among the signaling molecules utilized for the bidirectional communication, ATP and purinergic receptors play a central role in neuron-glia and glia-glia communications. However, due to lack of spatio-temporal information on the communications, its detailed mechanism still remains unknown. Then, we focused on P2Y1 receptor, a major astrocytic purinergic receptor whose activation causes huge Ca2+ signal. At first, we focused on neuron-astrocyte communication. To understand when and how P2Y1 receptor in astrocyte contributes to synaptic function, we used transgenic mice whose astrocyte overexpressed P2Y1 receptor specifically by Tet-off system (P2Y1OE) and imaged activities of neurons and astrocytes simultaneously using genetically encoded Ca2+ indicators in CA1 region of acute hippocampal slices. In astrocyte P2Y1OE mice, electrical stimulation of the Schaffer collateral resulted in fast Ca2+ rise in dendrites followed by slow-onset Ca2+ rise in astrocytes. The former was inhibited by TTX or D-APV/CNQX, and the latter was inhibited by TTX or MRS2179, a P2Y1 receptor antagonist, but still remained in the presence of the glutamatergic antagonists. These findings suggest that the dendritic Ca2+ signals were mediated by glutamatergic excitatory synaptic transmission, and the astrocytic ones were mediated by P2Y1 receptor, activated by released ATP presumably from presynaptic sites. Furthermore, duration of dendritic Ca2+ signals were increased in P2Y1OE, which was reduced by MRS2179, suggesting the increase in bidirectional commutation between neurons and astrocytes. To ask whether microglia play a role in the bidirectional communication, we depleted microglia by treatment with PLX5622, a CSF1R antagonist, and found larger Ca2+ elevation evoked by a P2Y1 receptor agonist and more P2ry1 gene expression in astrocytes. Furthermore, microglia depletion slowed recovery of extracellular ATP level from infusion of ATP, suggesting that microglia might negatively regulate neuron-astrocyte communication by altering P2Y1 receptor expression and extracellular ATP level. Overall, our data indicate that glial cells regulate synaptic transmission via P2Y1 receptor through bidirectional communication and gene expression.



    お名前 (必須)
    メールアドレス (必須)