Stars of the Brain: Uncovering the Complexity of Astrocytes

Author: Alyssa Lee

Editor: Keoni Andrews

Introduction

When you picture a brain cell, a "neuron" is likely what comes to mind. Historically, neurons have dominated the spotlight within neuroscience research. However, these famous cells would be unable to function without the presence of the "stars of the brain"- astrocytes. Astrocytes are the most populous macroglia in the central nervous system (CNS). Following their initial discovery by Rudolf Virchow in 1858, they were viewed as mere support staff, playing passive roles in supporting neuronal function. Recent advancements have radically redefined these macroglia. Today, astrocytes are recognised as necessary regulators of CNS health, playing active roles in synapse regulation, information processing within neuronal circuits and the formation/maintenance of the blood brain barrier (BBB) (Gradisnik & Velnar, 2023; Sofroniew & Vinters, 2010). The multifunctional behaviour of these cells have earned them the label of the ‘housekeepers’ of the CNS as they play vital roles in both physiological homeostasis and the immune response in pathological states (Verkhratsky et al., 2021).  

When the Stars Dim: Astrocytes dysfunction

Astrocytes are vital for overall CNS health. When they become dysfunctional or enter a state of prolonged reactivity, they actively contribute to the development and progression of various neurological or neuropsychiatric disorders.

In neurodegenerative diseases such as Alzheimer’s disease (AD), initially astrocytes attempt to protect the brain by assisting in amyloid-beta plaque clearance. However, after prolonged activity, they transform into a reactive, proinflammatory phenotype, producing cytokines that exacerbate disease progression (Kim et al., 2026; Kim et al., 2024). Restoring normal astrocytic function has been shown to help in the recovery of neuronal hyperactivity in AD, highlighting these cells as a major therapeutic target (Shah et al., 2022).

The health of astrocyte populations are also critical in neuropsychiatric contexts. Lima et al. (2014), modelled astrocyte pathology by poisoning astrocytes in the prefrontal cortex using an astrocyte specific toxin. Resulting in a decrease of astrocyte density, manifesting as schizophrenia-like cognitive symptoms, such as impaired working memory.

These examples highlight the importance astrocytes have in the CNS and how without their proper functioning issues arise.

A Tale of Two Matter Types: Astrocyte Heterogeneity

Astrocytes are complex cells and are highly heterogeneous on a morphological, genetic and functional level (Holt, 2023). A key part of this complexity is their spatial organisation, allowing them to carry out highly specialised, region-specific functions, a trait mapped as early as the prenatal stage (Schroeder et al., 2025). Traditionally, astrocytes can be classified into two basic morphological subtypes based on their neuroanatomical location: protoplasmic astrocytes and fibrous astrocytes, found in Fig 1 (Miller & Raff, 1984).

Table 1. A summary of Protoplasmic and Fibrous Astrocytes, highlighting their Location, Morphology and Primary Role.

	Protoplasmic Astrocytes	Fibrous astrocytes
Location	Gray Matter (GM)	White Matter (WM)
Morphology	Central soma. “Bushy” appearance, highly branched with primary and secondary/tertiary processes	Soma to one side. Straight, non-branched processes ending in small projections
Primary Role	Regulating neurotransmission, maintaining the BBB, CNS homeostasis	Production and maintenance of the myelin sheath

Figure 1. Tracings of protoplasmic and fibrous astrocytes. Protoplasmic astrocytes are highly branched with primary and secondary processes (branches), which split into many terminal processes (leaflets). Fibrous astrocytes are less branched with only primary processes that split into perinodal processes. The soma of protoplasmic astrocytes are found within the centre of the cell whereas the soma of fibrous astrocytes are found more towards the left with the length of the primary processes extending to the right.

Image by Verkhratsky et al. (2021)

Protoplasmic astrocytes and neurotransmission

Found widely distributed in the gray matter, protoplasmic astrocytes are critical for regulating synaptic transmission (Corkrum et al., 2020; Liu et al., 2021). Their endfeet ensheaths the synaptic terminals of neurons, forming the "tripartite synapse", a physiological model allowing bidirectional communication between the astrocyte and the pre- and post-synaptic neurons, shown in Fig 2.

Through the tripartite synapse, protoplasmic astrocytes actively regulate neurotransmitters, such as glutamate. While essential for normal brain processing and neuroplasticity, excess glutamate can cause excitotoxicity (de Ceglia et al., 2023; Pal, 2021). To prevent this, astrocytes express specialized membrane transporters (EAAT1 and EAAT2) that sweep up excess glutamate, degrade it into glutamine, and release it back for neuronal reuse (Adermark et al., 2022), shown in Fig 2. The reuptake and recycling cycle is vital as a disruption of neurotransmitter homeostasis, such as an excess in glutamate can lead to excessive Ca²⁺ influx in the postsynaptic neuron causing extreme neuronal firing and excitotoxicity (Teleanu et al., 2022).

Beyond simple uptake, they also actively release gliotransmitters, including glutamate, D-serine and ATP via Ca²⁺ regulated exocytosis to influence cognitive processing and synaptic plasticity (Harada et al., 2015; Sahlender et al., 2014). Furthermore, their endfeet enclose capillaries in the brain to form the outermost layer of the blood brain barrier (BBB), which allows them to regulate blood flow aligned with  synaptic demand (Chiareli et al., 2021).

Fibrous astrocytes and myelination

In contrast, fibrous astrocytes populate the white matter (WM). Although currently less researched than their gray matter (GM) counterparts, current evidence identifies them as key regulators of the production and maintenance of the myelin sheath. Their perinodal processes communicate with the nodes of Ranvier and interact with myelinating oligodendrocytes along the white matter tracks, facilitating the production and maintenance of myelin to actively support neuronal connectivity (Sofroniew & Vinters, 2010; Stogsdill et al., 2023). Additionally, astrocytes secrete promyelinating factors and regulate the maturation and migration of oligodendrocyte progenitor cells (Molina-Gonzalez & Miron, 2019), allowing for the proper development of myelin.

Dynamic Responses to Brain Injury

Astrocyte heterogeneity is not only apparent in their different functions but also in their response to neuroplasticity - changes in the brain. Astrocyte heterogeneity also dictates how the brain heals. During recovery from an ischemic stroke, gray matter astrocytes induce angiogenesis (new blood vessel formation), while white matter astrocytes do not (Gleichman et al., 2025). Furthermore, mechanical injury causes fibrous astrocytes to simplify their structures, while protoplasmic astrocytes do the opposite, becoming increasingly complex and branched (Sun & Jakobs, 2012).

Figure 2. A diagram of the tripartite synapse (pre- and post-synaptic neuron and astrocyte) illustrating how astrocytes regulate glutamate neurotransmission. Glutamate (brown circles) is released in vesicles from the presynaptic terminal via exocytosis. The glutamate receptor on the astrocytes sense an excess of glutamate in the extrasynaptic space which triggers the reuptake of glutamate via express glutamate transporters excitatory amino acid transporter 1 (EAAT1) and transporters excitatory amino acid transporter 2 (EAAT2). The rest of the glutamate is taken up by the postsynaptic neuron. Glutamate taken up by the astrocyte is degraded into glutamine and released into the extrasynaptic space for neuronal uptake. Created using BioRender

Heterogeneity within GM and WM brain regions

The complexity deepens when looking within these broad categories. White matter astrocytes can be further divided by gene expression, as some are dedicated to axonal support, while others focus on cell proliferation (Bocchi et al., 2025). Similarly, gray matter astrocytes exhibit laminar specificity, displaying distinct shapes and genetic profiles depending on their specific layer within the neocortex (Lanjakornsiripan et al., 2018).

Conclusion

Taken together, research has revealed astrocytes are far from simple support units but are a diverse, highly specialised population of cells vital for CNS health and neural mechanisms. As GM and WM astrocytes govern different brain functions and respond uniquely to neurological insults, studying them as distinct populations is essential. Moving forward, continued research into astrocyte heterogeneity, particularly the under-explored WM populations, is imperative for developing targeted therapeutics that can prevent astrocytes from losing their protective mechanisms during disease or prevent their dysfunction/loss.

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