NEURO2022参加報告 薬理学教室 檀上洋右
Glial cells are essential for the organization of synaptic connections and healthy brain development. They control the excitatory / inhibitory synaptic balance and assemble neural circuity by synaptic formation and elimination. We have recently revealed that astrocytes form excitatory synapses in the adult injured brain through mGluR5 signaling. However, in the healthy brain, astrocytic mGluR5 is expressed in the only limited time-window of the postnatal developmental stage. Therefore, we investigated whether and how astrocytic mGluR5 destines the subsequent synaptic assembly using astrocyte-specific mGluR5 KO mice (astro-mGluR5 cKO). Unexpectedly, the number of excitatory synapses did not alter much in astro-mGluR5 cKO, instead, the number of inhibitory synapses decreased significantly in astro-mGluR5 cKO throughout ages. Interestingly, this decrease was due to phagocytosis by microglia, not by astrocytes. In fact, microglia frequently engulfed inhibitory synaptic elements in the critical period in astro-mGluR5 cKO. Although astrocytic mGluR5 expression was a transient event limited in the critical period, its deficient affected the rest of the life, and in fact, behavioral dysfunction was observed in adult astro-mGluR5 cKO mice. Next, we explored mechanisms underlying astrocytic mGluR5 deficiency-mediated microglial engulfment. We screened several astrocyte-related molecules and focused on IL7 as a candidate for such a molecule, because it dramatically decreased in astro-mGluR5 cKO. In fact, treatment of microglia with IL7 decreased expression of several engulfment-related genes. Hence, we conclude that astrocytes organize inhibitory network in the critical period by tuning microglial phagocytic activity via IL7-mediated mechanisms. 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.