From Neurons to Astrocytes: The Shift of Focus in Stroke

If you think about it, blood vessels are the freeways of the body. The vast array of vasculature enables molecules to reach important destinations (organs) quickly. But, if a small part of the freeway is blocked suddenly, then the constant flow of traffic suffers and previously desired exits now become inaccessible. When such a traffic jam occurs inside a blood vessel en route to the brain, the brain region previously receiving blood and oxygen is now devoid of it. Such a phenomenon where a blood clot obstructs blood flow to a part of the brain is called ischemic stroke.

Within a few seconds of ischemia, the affected brain region becomes stressed, and the neurons in the area release large amounts of the excitatory neurotransmitter, glutamate. This episode is called excitotoxicity and is the final outcry from neurons before they take an apoptotic path towards cellular death, causing permanent damage to that brain region. Attempts to combat this glutamate surge by the use of glutamate receptor antagonists (blockers) have been unsuccessful in human clinical trials, mostly because of the other important functions that glutamate has in the brain. Recently, in an effort to mitigate ischemic damage, researchers have shifted focus from neurons to another integral cell type found in the brain: astrocytes.

Astrocytes, the brain’s predominant glial cell type, not only offer structural integrity, but also help support neuronal function. Membranous processes of the astrocytes wrap around neurons to form a tripartite synapse: presynaptic neuron, postsynaptic neuron, and astrocyte. Upon activation by neurotransmitters at the synapse, astrocytes release a variety of molecules called gliotransmitters. A research team at Tufts University recently tapped into this astrocytic signaling and studied its contribution to ischemic damage after stroke.

The researchers developed genetically modified mice that had no astrocytic expression of the exocytosis-mediating protein complex, SNARE. This meant that the astrocytes of these mice could not release (or exocytose) any gliotransmitters and had no astrocytic signaling. Ischemic stroke was then induced in these mice. After careful observation, the researchers found that mice with mutated astrocytic SNAREs showed less cellular damage from stroke when compared to control mice. These mice also performed significantly better in sensory-motor behavioral tests! These results show that the absence of astrocytic signaling results in reduced injury from stroke and suggest that astrocytes normally contribute towards ischemic damage along with neurons!

These results corroborate the involvement of astrocytes in stroke and show promise for a new target in stroke-related therapy. To add to this, the researchers also observed that while ischemic neurons undergo apoptosis, astrocytes maintain their structural integrity for hours after stroke, making them a strong candidate for therapeutic manipulation.

Historically, neurons have been in the limelight of stroke research. But over the recent years, after it was discovered that astrocytes can also modulate glutamate signaling, the field saw a shift of focus from neurons to astrocytes. In science, just as in everyday life, there still remain hidden potentials in things that we previously overlooked!

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References:

Hines D.J. & Haydon P.G. (2013). Inhibition of a SNARE-Sensitive Pathway in Astrocytes Attenuates Damage following Stroke, Journal of Neuroscience, 33 (10) 4234-4240. DOI:10.1523/JNEUROSCI.5495-12.2013

Images adapted from www.webmd.com and made by Anita Ramanathan.