Astrocytes, Alzheimer’s and autism

Astrocytes—cells in the cerebral cortex—have distinct layers across the cerebral cortex that provide evidence of their specialization across the brain. The cerebral cortex of the mammalian brain contains neurons, the cells responsible for transmitting information throughout the body. The 10 billion to 14 billion neurons of the human cerebral cortex are organized into six layers, with distinct populations of neurons in each layer that correspond to their function.

A recent article in Nature Neuroscience titled “Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map” sheds light on the role of cells such as astrocytes in neurological disorders, including Alzheimer’s disease, multiple sclerosis and autism. The study—supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, National Institutes of Health, NINDS Informatics Center for Neurogenetics and Neurogenomics, Wellcome and the European Research Council—elucidates the role of glial cells.

Before the study, there had been little investigation into the question of whether or not glial cells across different layers showed different cellular properties. A type of glial cell, astrocytes are so named because of their star-shaped structure. The researchers developed a new methodological approach to provide a detailed view of the organization of astrocytes. They used nucleic acid imaging on mouse and human brain samples at the University of Cambridge to map how new genes are expressed within tissue. The maps were then combined with single-cell genomic data at the Wellcome Sanger Institute to extend the molecular description of astrocytes. Finally, they combined the data sets to create a three-dimensional, high-resolution picture of astrocytes in the cerebral cortex.

The researchers discovered that astrocytes, which are not uniform, take distinct molecular forms related to their location in the cerebral cortex. Astrocytes are organized into multiple layers, but the boundaries of astrocyte layers are not identical to the neuronal layers. The astrocyte layers have less sharply defined edges and overlap the neuronal layers.

As the article explained, the researchers “developed a high-content pipeline, the large-area spatial transcriptomic map, which can quantify single-cell gene expression in situ.” By screening 46 candidate genes for astrocyte diversity across the mouse cortex, they “identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons.”

The team determined that, “Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.”

According to Dr. Omer Bayraktar, group leader at the Wellcome Sanger Institute, “The discovery that astrocytes are organized into layers that are similar, but not identical to, neuronal layers redefines our view of the structure of the mammalian brain. The structure of the cerebral cortex can no longer simply be seen as the structure of neurons. If you want to properly understand how our brains work, you have to consider how the astrocytes are organized and what role they play.”

He added, “As well as increasing our understanding of brain biology, the findings will have implications for the study and treatment of human neurological disorders. Over the past decade, glial cells, rather than neurons, have been heavily implicated in diseases such as Alzheimer’s and multiple sclerosis.”

Prof. David Rowitch, senior author of the study and head of pediatrics at the University of Cambridge, added, “This study shows that the cortical architecture is more complex than previously thought. It provides a basis to begin to understand the precise roles played by astrocytes, and how they are involved in human neurodevelopmental and neurodegenerative diseases.”