Human astrocytes: structure and functions in the healthy brain

Abstract

Data collected on astrocytes' physiology in the rodent have placed them as key regulators of synaptic, neuronal, network, and cognitive functions. While these findings proved highly valuable for our awareness and appreciation of non-neuronal cell significance in brain physiology, early structural and phylogenic investigations of human astrocytes hinted at potentially different astrocytic properties. This idea sparked interest to replicate rodent-based studies on human samples, which have revealed an analogous but enhanced involvement of astrocytes in neuronal function of the human brain. Such evidence pointed to a central role of human astrocytes in sustaining more complex information processing. Here, we review the current state of our knowledge of human astrocytes regarding their structure, gene profile, and functions, highlighting the differences with rodent astrocytes. This recent insight is essential for assessment of the relevance of findings using animal models and for comprehending the functional significance of species-specific properties of astrocytes. Moreover, since dysfunctional astrocytes have been described in many brain disorders, a more thorough understanding of human-specific astrocytic properties is crucial for better-adapted translational applications.

Keywords: Astrocytes; Brain; Human; Neuroglial interactions; Physiology.

Fig. 1

Distinct classes of astrocytes in the human brain. a Location of the four distinct types of human astrocytes within different layers of the cortex. Scale bar 100 µm. b Interlaminar astrocytes in the human occipital cerebral cortex. The dashed line indicates the limit of layer I. Scale bar 100 µm. c Graphical representation of mouse (top) and human (bottom) cortical protoplasmic astrocytes, showing that human astrocytes are almost threefold larger and more symmetrical than mouse astrocytes. Scale bar 25 µm. d Representative human protoplasmic astrocyte diolistically labelled. Inset colocalization with GFAP (green). Scale bars 20 µm. e Representative varicose projection astrocyte (left) and enlarged view of the area indicated by the yellow box, which highlights the varicosities along the processes. Scale bars left, 20 µm; right, 10 µm. f Representative human fibrous astrocyte. Scale bar 20 µm. [a, c adapted from (Oberheim et al. 2006); b from (Colombo and Reisin 2004); d–f adapted from (Oberheim et al. 2009)]

Fig. 2

Genetic and functional specificities of human astrocytes. Schematic representation of genetic and functional specificities of human astrocytes in synapse formation, Ca²⁺ signalling, electrophysiological properties, gliotransmission, gap junction coupling, neurotransmitter uptake and recycling, and metabolism. mRNAs with higher expression in human astrocytes are indicated in red. ACh acetylcholine, AChR acetylcholine, AMYB2 amylase α 2B, APOC2 apolypoprotein C-2, CA2 carbonic anhydrase 2, CB1 cannabinoid receptor 1, Cm membrane capacitance, Cxs connexins, EAATs excitatory amino acid transporter, GDH1/2 glutamate dehydrogenase 1/2, Glu glutamate, HR Histamine receptor, mGluR5 metabotropic glutamate receptor 5, MRVI1 (or IRAG) inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate, NMDAR NMDA receptor, P2R purinergic receptor, RGN regucalcin, Rm membrane resistance, RyR ryanodine receptor, THBS thrombospondins, Vm membrane potential