Abstract
Propofol is a widely used anesthetic in the clinic while several studies have demonstrated that propofol exposure may cause neurotoxicity in the developing brain. However, the effects of early propofol exposure on cerebellar development are not well understood. Propofol (30 or 60 mg/kg) was administered to mice on postnatal day (P)7; Purkinje cell dendritogenesis and Bergmann glial cell development were evaluated on P8, and granule neuron migration was analyzed on P10. The results indicated that exposure to propofol on P7 resulted in a significant reduction in calbindin-labeled Purkinje cells and their dendrite length. Furthermore, propofol induced impairments in Bergmann glia development, which might be involved in the delay of granule neuron migration from the external granular layer (EGL) to the internal granular layer (IGL) during P8 to P10 at the 60 mg/kg dosage, but not at the 30 mg/kg dosage. Several reports have suggested that the Notch signaling pathway plays instructive roles in the morphogenesis of Bergmann glia. Here, it was revealed that propofol treatment decreased Jagged1 and Notch1 protein levels in the cerebellum on P8. Taken together, exposure to propofol during the neonatal period impairs Bergmann glia development and may therefore lead to cerebellum development defects. Our results may aid in the understanding of the neurotoxic effects of propofol when administrated to infants.
Highlights
The cerebellum is characterized by laminated structures, and its abnormal morphogenesis may lead to deficits related to disorders such as Dandy-Walker Malformations, Joubert Syndrome and other congenital spinocerebellar ataxias (Millen and Gleeson, 2008)
We found that Jagged1 and Notch1 levels were considerably decreased in the cerebella at P8 following exposure to propofol at the 30 mg/kg dose compared to vehicle treatment; a further reduction was detected after treatment with the 60 mg/kg dose (Figure 8A)
We studied the effects of propofol exposure on cerebellar development during early life
Summary
The cerebellum is characterized by laminated structures, and its abnormal morphogenesis may lead to deficits related to disorders such as Dandy-Walker Malformations, Joubert Syndrome and other congenital spinocerebellar ataxias (Millen and Gleeson, 2008). To establish proper lamination and circuitry, important events such as neuronal differentiation, morphogenesis, and migration need to be precisely regulated during cerebellar development (Altman and Winfree, 1977; Buffo and Rossi, 2013). Mouse cerebellar development continues until 3 weeks after birth. During this postnatal period, cerebellar cells undergo sequential development steps in spatially well-defined regions. At the early postnatal stage, granule cell precursors are the most abundant in the external granular layer (EGL), followed by an inward radial migration along the Bergmann glial radial fibers to their destination, the internal granule layer (IGL; Komuro et al, 2001; Buffo and Rossi, 2013). By the end of the third postnatal week, the EGL disappeared and three well-defined neuronal layers have formed (Qiu et al, 2010)
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