| 研究実績の概要 |
Maternal immune activation (MIA) triggered by viral infection during pregnancy is known to be a risk factor for neurodevelopmental disorders (NDDs). Although cerebellar structural and functional differences are associated with NDDs, little is known about the effects of MIA on fetal cerebellar development and its underlying mechanisms. Here, I found that polyinosinic:polycytidylic acid (poly(I:C))-induced MIA causes motor alterations in the offspring in adulthood. Moreover, single-cell RNA sequencing and immunofluorescence analyses revealed that MIA impairs the migration and generation of glutamatergic cerebellar nuclei (CN) neurons expressing Lhx9 and Meis2 in cerebellar development. Importantly, administration of interferon (IFN)-β, a type-I IFN produced in MIA, also mimics these changes in cerebellar development. While seemingly contradictory, the loss of type-I IFN signaling by administration of a neutralizing antibody of the receptor also restricts neuronal migration in cerebellar development. Finally, administration of IFN-β to pregnant mice results in motor alteration in the offspring. These findings suggest that although baseline type-I IFN signaling is required for normal cerebellar development, the excessive production of IFN-β in response to MIA disrupts cerebellar development and leads to motor behavioral abnormalities in the offspring.
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