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β-adrenergic signaling promotes gray matter astrocyte maturation in mouse

Abstract

Astrocytes play essential roles in the developing nervous system, including supporting synapse maturation. These astrocyte support functions emerge coincident with brain maturation and may be tailored in a region-specific manner. For example, gray matter astrocytes have elaborate synapse-associated processes and are morphologically and molecularly distinct from white-matter astrocytes, raising the question of whether there are unique environmental cues that promote their identity and synaptogenic function. We previously identified adrenergic receptors as preferentially enriched in developing gray versus white matter astrocytes, leading us to hypothesize that noradrenergic signaling might promote the functional maturation of gray matter astrocytes. We first characterized noradrenergic projections during postnatal brain development in mouse and human, finding that they are preferentially enriched in gray matter and increase in density in concordance with astrocyte maturation. RNA-sequencing revealed that astrocytes in both species expressed ɑ and β adrenergic receptors. We found that stimulation of β adrenergic receptors increased the primary branching of rodent astrocytes in vitro, while conditional knockout of the β1 adrenergic receptor in astrocytes in vivo reduced the size of gray, but not white matter, astrocytes, and led to dysregulated sensorimotor integration in female animals. These studies suggest that adrenergic signaling during development directly impacts astrocyte morphology and can impact behavior. More broadly, they demonstrate a mechanism through which environmental cues impact astrocyte development. Given the key roles of norepinephrine in brain states such as arousal, stress, and learning, these findings could prompt further inquiry into how developmental stressors impact astrocyte development and adult brain function.

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