Glial ER and GAP junction mediated Ca2+ waves play a vital role in maintaining brain excitability

The search for neurodegenerative disease therapies has yielded only a few treatment solutions for patients with no new major drugs or therapeutic breakthroughs for Parkinson’s disease and Alzheimer’s disease. The complex etiology of these diseases requires innovative new thinking. Recently there has been a push to understand the relationship between astrocytes and neurodegenerative disorders which has set the stage for new therapeutic development opportunities to complement current drug development approaches that solely target disease neurons.

Astrocytes, a subclass of non-neuronal cells collectively termed glial cells, constitute a significant proportion of the central nervous system cell population. It is now known that glial cells play an important role in brain homeostasis, and they are not just there to support the neurons. Thus, one of the most common glial subtypes, astrocytes, help control the blood-brain barrier, the influx of nutrients, and even neuronal excitability. In addition, astrocytes can considerably modulate the working of neurons. However, the underlying mechanism in which they modulate various brain functions remains poorly understood.

To expand and highlight the important functional role of astrocytes in the CNS and show that they can induce or rescue neurons from disease states, Tel Aviv University scientists Dr. Shirley Weiss, Lauren Clamon, Julia Manoim, Kiel Ormerod, and Moshe Parnas in collaboration with Professor J. Troy Littleton from the Massachusetts Institute of Technology studied the role of Calcium (Ca²⁺) signaling in astrocytes. Early studies show that Ca²⁺ activity in glial cells that directly contact neurons plays an important role in regulating neural activity and seizures. However, collectively, Dr. Weiss’s studies reveal that Ca²⁺ activity has different dynamics in different glial subpopulations and occurs via different cellular mechanisms. Moreover, studies show that there are different sources of this Ca²⁺. Thus, Ca²⁺ may enter the cells from the plasma membrane via Ca²⁺ channels, or it may be released from Ca²⁺ in the endoplasmic reticulum or even mitochondria. Understanding the role of these different Ca²⁺ waves from different Ca²⁺ sources is essential in understanding how glial cells modulate brain development and functioning.

The research team used the Drosophila model to study the role of Ca²⁺ signaling in glial cells. It is common to use the Drosophila model in research due to the simplicity of its brain and ease of genetic manipulation. Moreover, Drosophila CNS is separated from its lymph with the help of a barrier that is structurally similar to the blood-brain barrier (BBB) in the mammalian brain.

Thus, the authors used Drosophila model and utilized imaging techniques to visualize the Ca²⁺ influx or waves in perineurial glia  forming an important part of BBB in the Drosophila brain. The study found an important role of ER Ca²⁺ release in maintaining neural activity. They also found that the activity varied in different parts of the brain. The knockdown of the release of Ca²⁺ via ER store-operated Ca²⁺ entry (SOCE) caused greater susceptibility to seizures. Similarly, knockdown of GAP junctions that facilitate the spread of Ca²⁺ waves, also increased seizure susceptibility. On the contrary, normalization of the Ca²⁺ release from the internal stores also normalized the propagation of signals to the neighboring glial cells, thus demonstrating that these Ca²⁺ signaling events are essential for the normal functioning of the nervous system.

The authors conducted elegant cellular and molecular experiments to investigate the function of glial cells. Indeed, understanding the role of glial cells in brain homeostasis and functioning would help find effective remedies for various brain disorders. Thus, these findings may help manage neurodegenerative disorders, epilepsy, migraine headaches, and more. Moreover, it is likely that in the near future, these findings may help develop innovative drugs that target glial cells and modulate their function specifically, compared to decades-long of targeting only the neurons and neurotransmitters, an approach that has failed to help in many brain disorders.