Regional Astrocyte Allocation Regulates CNS Synaptogenesis and Repair

Abstract

Astrocytes, the most abundant cell population in the central nervous system (CNS), are essential for normal neurological function. We show that astrocytes are allocated to spatial domains in mouse spinal cord and brain in accordance with their embryonic sites of origin in the ventricular zone. These domains remain stable throughout life without evidence of secondary tangential migration, even after acute CNS injury. Domain-specific depletion of astrocytes in ventral spinal cord resulted in abnormal motor neuron synaptogenesis, which was not rescued by immigration of astrocytes from adjoining regions. Our findings demonstrate that region-restricted astrocyte allocation is a general CNS phenomenon and reveal intrinsic limitations of the astroglial response to injury.

Topological analyses in APP/PS1 mice reveal that astrocytes do not migrate to amyloid-β plaques

“…First, the g(r) function indicates that the domain-based arrangement of astrocytes is caused by exclusion forces. Second, after mathematically modeling the effect of plaques on such domains, we did not find that plaques attract astrocytes, supporting recent observations suggesting that adult astrocytes do not actively move to sites of injury (3,4). Although the slight local repulsion caused by plaques seems to have a negligible impact on the global astrocyte topology at low or average plaque loads, the simulations indicate that at the heaviest plaque loads detected in humans the local repulsion may put stress on interastrocyte interactions.…”

“…The idea that astrocytes are attracted to plaques is an extension of the notion that astrocytes migrate to zones of injury (1,2) and is mostly based on the immunohistochemical observation that amyloid-β deposits are typically surrounded by concentric rings of "reactive astrocytes," defined by increased GFAP immunoreactivity and hypertrophy. However, recent studies question the capacity of astrocytes to move (3,4). These suggest instead that astrocytes may be restricted to their birthplace (3), which in the neocortex seems to be within neuronal columns derived from radial glia (5).…”

“…However, recent studies question the capacity of astrocytes to move (3,4). These suggest instead that astrocytes may be restricted to their birthplace (3), which in the neocortex seems to be within neuronal columns derived from radial glia (5). Recent stereological assessments of astrocytes in Alzheimer's disease suggest that their most prominent change is phenotypic (i.e., GFAP immunoreactivity and hypertrophy) rather than proliferative (6).…”

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord

“…During this period, after the decline in neurogenesis, neural tube progenitors are massively engaged in astrocytic and oligodendrocytic differentiation, in a regionally restricted manner (Zhou and Anderson, 2002;Lu et al, 2002;Hochstim et al, 2008;Tsai et al, 2012;Rowitch and Kriegstein, 2010).…”

Glial Contributions to Neural Function and Disease

“…More recently, methodologies for genetically labeling astrocytes using astrocytespecific drivers (e.g. glial fibrillary acidic protein and Aldh1L1) have become available (4,5) and have provided new insights into astrocyte development, structure, and function. These tools may also prove to be extremely useful in the application of proteomic approaches to understanding astrocyte function.…”