central nervous system (CNS) consists of a large number of non-neuronal cells called glial cells . Astrocytes cover the entire central nervous system , exert key homeostasis functions, and display complex "burned" morphology, which is their characteristic. Unlike highly diverse CNS neurons, astrocytes have been historically considered essentially homogeneous.
Although recent studies have challenged this view, diversity, similarity, or morphology of astrocytes in the central nervous system of any species has not been extensively evaluated. Therefore, an important goal of is to strictly understand the molecular similarities and differences between astrocytes in the CNS, determine how they affect astrocyte morphology, and determine the relationship between these characteristics and normal and disease conditions.
Recently, the research team of the Department of Physiology at the University of California, Los Angeles published a study in Science. determined the shared and regionally specific astrocyte genes and functions, and explored the cellular origins of its regional diversity.
Astrocytes and Anatomy Evaluation
Researchers evaluated astrocytes in 13 regions of CNS in adult mice as follows: (1) Astrocyte-neuron density and astrocyte marker expression in different regions. (2) Astrocyte-specific RNA sequencing, tissue RNA sequencing and single-cell RNA sequencing evaluated molecular profiles and signaling pathway . (3) Record the morphology of astrocytes and identify gene networks related to morphological complexity.
Results found that was observed to vary the density of astrocytes across the brain and spinal cord between different regions. There is a significant but modest double difference between the regions [Fig.1C,D]. Moreover, there is no one-to-one proportional relationship between interneurons and astrocyte density in each region [Fig.1H]. It is shown that the astrocyte density in each region of does not simply change with neuronal density, but is laid out in the central nervous system with moderate changes, which may reflect its homeostatic function.
Figure 1 Astrocyte density and astrocyte-neuron ratio in the central nervous system of mice
CNS shared or unique genes and pathways
Next, 4314 genes rich in astrocytes were identified through sequencing, of which 825 were common in 13 regions and called "shared" genes. Gene enrichment analysis found that the top pathway is related to neurotransmitter homeostasis, cholesterol biosynthesis and glucose metabolism [Fig.2D].
In addition, the researchers identified the first 10 marker genes from the brain, brainstem and spinal cord, as well as the region-specific astrocyte marker genes in each brain region [Fig.2H].
Figure 2 Astrocyte sharing and unique molecular characteristics and mechanisms in CNS
Evaluation of astrocyte diversity
Is there a subpopulation of astrocytes in the region? Do different combinations of subpopulation contribute to regional properties of astrocytes? The researchers found that seven astrocyte subclusters (AST1 to AST7) were shared in the CNS region, representing the cortex, hippocampus, and striatum [Fig.3C,D].
A key feature of astrocytes is the complexity of their morphology. By recording the two-dimensional (2D) morphological characteristics of astrocytes from 13 central nervous system regions, it was found that the number of major branches of each astrocyte in the 13 CNS regions did not differ, but there were significant differences in morphological complexity. And different astrocyte subclusters contribute to the morphological characteristics of astrocytes [Fig.3G].
Figure 3 Origin of astrocyte diversity
Astrocyte morphology-related genes in AD
Finally, several downregulated genes in AD disease model are related to genes related to astrocyte morphology [Fig.4B], which means that the regional size of astrocytes in AD may decrease. Compared with wild-type mice, the AST1 subpopulation in APP/PS1 mice was significantly increased and the AST6 subpopulation was significantly decreased [Fig.4D].
In addition, the first 10 astrocyte region size-related genes overlapping with CNS disease-related genes [Fig.4J] suggests that astrocyte morphological changes may be a generally underestimated feature of a variety of CNS disorders.
Figure 4 Astrocyte morphology-related genes in AD mouse models, human AD and other central nervous system diseases
Summary
This study provides comprehensive molecular data, which will allow many new types of experiments to explore the core characteristics of astrocytes in the central nervous system, , especially those specific to those regions, and how they are associated with the dynamics of neural circuits in specific regions of the central nervous system and biophysics .
References:
Endo, Fumito et al. “Molecular basis of astrocyte diversity and morphology across the CNS in health and disease.” Science (New York, N.Y.) vol. 378,6619 (2022): eadc9020. doi:10.1126/science.adc9020
compiled by: Young (brainnews creative team)
review: Simon (brainnews editorial department)
