Astrocytes and disease: a neurodevelopmental perspective

Abstract

Astrocytes are no longer seen as a homogenous population of cells. In fact, recent studies indicate that astrocytes are morphologically and functionally diverse and play critical roles in neurodevelopmental diseases such as Rett syndrome and fragile X mental retardation. This review summarizes recent advances in astrocyte development, including the role of neural tube patterning in specification and developmental functions of astrocytes during synaptogenesis. We propose here that a precise understanding of astrocyte development is critical to defining heterogeneity and could lead advances in understanding and treating a variety of neuropsychiatric diseases.

Figure 1.

Astrocytes are morphologically heterogeneous. A protoplasmic astrocyte is shown in close connection with a neuron and a capillary, constituting the so-called “neurovascular unit” and highlighting the roles of astrocytes in developmental synaptogenesis and in modulating the BBB. (Right) A fibrous astrocyte is shown in a white matter tract, where it may interact with oligodendrocytes to promote myelination.

Figure 2.

Neural tube patterning determines astrocyte identity in the developing spinal cord and influences astrocyte regional investment in adulthood. The neural tube is patterned via secretion of morphogens, including sonic hedgehog (SHH) from the floor plate and BMP/Wnts from the roof plate. This sets up domains of transcription factor expression, at least some of which have been shown to relate to specific white matter astrocyte subtypes in the ventral neural tube (VA1, VA2, and VA3). Whether this regional investment of astrocytes applies throughout the dorsal–ventral axis and whether it persists into adulthood is unknown. The right panel shows a hypothetical outcome, assuming strictly radial astrocyte migration.

Figure 3.

Astrocyte morphology and function changes across developmental time. Neuroepithelial cells give rise to radial glia, which generate first neurons, and then become glial-committed, giving rise to precursors that proliferate and diversify into fibrous and protoplasmic astrocytes, which then go through a protracted stage of postnatal maturation. Astrocyte precursors at these different stages of maturation serve well-established stage-specific roles in assisting myelination and synaptogenesis and may also influence other functions, such as neuronal migration, pruning, and so forth. Well-established adult roles for astrocytes, including supporting neuronal survival and homeostasis, likely develop in parallel.

Figure 4.

Recapitulation of human astrocyte diversity in vitro. Human stem cell-derived neuroepithelial cells (NE) can be patterned into region-specific neural progenitor subtypes by the addition of morphogens. After an extended differentiation into a gliogenic-restricted stage, the resultant astroglial cells retain the positional code, similar to cells generated throughout the entire axis of the neural tube. This culture system allows for studies of the functional consequences of astrocyte diversity in the absence of unknown environmental variables that are present in vivo and provides a human disease model by using astrocytes generated from patient-specific induced pluripotent stem cells.