Don’t forget about the stars in your brain!

Figure 1: Immunohistochemistry stain of astrocytes (Oksanen, 2017, Stem Cell Reports).

In the late 19th century, Santiago Ramón y Cajal aided in the formation of the neuron doctrine, a theory which used evidence from neuronal staining techniques to confirm that neurons are each separate entities and not one continuous fusion of cells. These separations allow neurons to have highly flexible communication over long distances. However, this theory leaves out key players in the neural network, such as astrocytes. Astrocytes are the predominate glial cell type of the nervous system that integrate communication with neurons to ensure prompt and accurate signaling. While astrocytes have not always been the highlighted cell type in neural research, these glial cells, named for their star shape, are nothing short of superstars in the brain. Beyond their role in supporting neurons and brain homeostasis, astrocytes communicate with neurons to maintain normal brain function. In the absence of astrocyte-neuron relationships, neural diseases and disorders such as Huntington’s disease Alzheimer’s disease can develop1.

Astrocytes receive input from up to 140,000 neuronal synapses simultaneously2. Unlike neuron-to-neuron communication, astrocytes do not use action potentials (electrical impulses propagated by the opening of ion channels between cells). Instead, astrocytes respond to neurotransmitters through calcium signaling, allowing them to secrete gliotransmitters3,4. Gliotransmitters are small chemical messengers released by glia and are especially significant because they play a major role in synaptic plasticity2,3. Huntington’s disease is a motor and cognitive impairment disease that showcases the indispensability of astrocyte-neuron communication. In Huntington’s disease, there is a decrease in the number of neurotransmitter transporters on astrocytes, leading to decreased uptake from the cleft between neurons5. Leaving this excess of neurotransmitters in the space between neurons leads to increased neuronal excitability and consequently dysregulates calcium signaling in astrocytes5. This result can then exacerbate cognitive impairment in Huntington’s disease.

Figure 2: Astrocytes are vital for cerebral metabolism (Harada, 2016, Frontiers in Neuroscience).

Astrocyte-neuron communication is also vital for metabolic regulation in the brain. While neurons cannot store glucose for later usage, astrocytes can readily convert glucose to glycogen as energy storage. When neurons run low on oxygen, astrocytes convert their glycogen back to usable energy for surrounding neurons6. The breakdown of glycogen is important for learning and memory7 and consequently, impairments in the creation and breakdown of glycogen have been associated with Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative disease where neurons begin to die prematurely, leading to cognitive impairment. Deficiencies in glycogen storage by astrocytes partially contribute to the neuronal death in Alzheimer’s disease, diminishing memory8. While the death of neurons is often the main focus in studying Alzheimer’s disease, it is worth noting that it is the change in cerebral metabolism due to astrocyte dysregulation that may be the actual cause of neuron death. The necessity for neurons to localize near astrocytes for an additional energy supply and regulation of glucose delivery showcases the importance of astrocytes in preserving brain function.

While the neuron doctrine from the 19th century surely set a precedent for a neuron-centric view of the entire nervous system, more recent evidence sheds light on the essential role of astrocytes for brain homeostasis. Astrocytic functions like communication with neurons and metabolism are vital to cerebral survival. Their multimodal communication with neurons allows for high complexity and adaptability in the brain, crucial for homeostasis, metabolism, and cell signaling. Interestingly, one study ablated astrocytes in mice, resulting in a vast death of neurons9. Such studies provide irrefutable evidence astrocytes are important for brain health and should not be forgotten. Scientists are uncovering a role for astrocytes in a number of other diseases such as depression, epilepsy, schizophrenia, and addiction1. As we learn more about these underappreciated cells, we realize that astrocytes truly live up to their name as “stars”.

By Rebecca Fleeman, Associate Editor

References

1.        Verkhratsky, A., Nedergaard, M. & Hertz, L. Why are Astrocytes Important? Neurochem. Res. 40, 389–401 (2015).

2.        Allen, N. J. Synaptic plasticity: Astrocytes wrap it up. Curr. Biol. 24, R697-9 (2014).

3.        Blanco-Suárez, E., Caldwell, A. L. M. & Allen, N. J. Role of astrocyte-synapse interactions in CNS disorders. J. Physiol. 595, 1903–1916 (2017).

4.        Allen, N. J. & Barres, B. A. Glia — more than just brain glue. Nature 457, 675–677 (2009).

5.        Jiang, R., Diaz-Castro, B., Looger, L. L. & Khakh, B. S. Dysfunctional Calcium and Glutamate Signaling in Striatal Astrocytes from Huntington’s Disease Model Mice. J. Neurosci. 36, 3453–70 (2016).

6.        Prebil, M., Jensen, J., Zorec, R. & Kreft, M. Astrocytes and energy metabolism. Arch. Physiol. Biochem. 117, 64–69 (2011).

7.        Bak, L. K., Walls, A. B., Schousboe, A. & Waagepetersen, H. S. Astrocytic glycogen metabolism in the healthy and diseased brain. J. Biol. Chem. 293, 7108–7116 (2018).

8.        Li, C. et al. Decreased Glycogenolysis by miR-338-3p Promotes Regional Glycogen Accumulation Within the Spinal Cord of Amyotrophic Lateral Sclerosis Mice. Front. Mol. Neurosci. 12, 114 (2019).

9.        Allen, N. J. Astrocyte regulation of synaptic behavior. Annu. Rev. Cell Dev. Biol. 30, 439–63 (2014).

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