As the fundamental building blocks of the nervous system, neurons have long been at the center of neurobiological research, forming intricate networks within living organisms and displaying key properties such as excitability. Excitability is defined as the ability to generate an action potential, a process triggered when a neuron at rest receives a stimulus surpassing the threshold value, leading to changes in the cell membrane, known as the action potential. During this process, the interactions between sodium (Na+) and potassium (K+) ions through voltage-gated ion channels facilitate depolarization and repolarization, driving the electrochemical events at the cell membrane, ultimately resulting in the neuron entering an excited state. It is known that the dysregulation of excitability leads to many serious health problems, such as epilepsy, chronic pain, neuropsychiatric diseases, and stroke. Dorsal root ganglia (DRG) are the groups of somatosensory neurons located at the dorsal roots of the spinal cord, responsible for transmitting sensory inputs to the central nervous system (CNS). These neurons primarily function to relay sensory stimuli to the CNS. Schwann cells, a type of glial cell found in the peripheral nervous system, enclose neurons along their axons either through myelination or in a non-myelinated form. Previously known for their role in supporting neurons and speeding up neural transmission, Schwann cells have now been shown to enhance neuronal excitability through the secretion of signaling molecules.
Kantarci and her research colleagues examined the mechanisms that encourage neuronal excitability, and they demonstrated that the prostaglandin E2 molecule (PGE2) which secretes from Schwann cells, promotes neuron excitability during development. It was discovered that highly purified embryonic DRG neurons, which lacked Schwann cells, were hypoexcitable and unable to generate action potential sequences. However, when these DRG neurons were exposed to an environment containing signaling molecules secreted by Schwann cells, they regained normal expression levels of genes essential for neuronal function, including voltage-gated sodium channels (NaVs), and were able to produce action potential sequences. Disrupting the signal pathway in which PGE2 functions as a signaling molecule led to NaV expression, neuronal hypoexcitability, and a range of neurodevelopmental defects. Additionally, mice deficient in PGE2 production within Schwann cells exhibited developmental abnormalities across all sensory neuron subtypes, as well as behavioral impairments.
In this study, researchers have identified the signaling pathway wherein PGE2 secreted by Schwann cells, acts as a signaling molecule to stimulate NaV expression and promote neuronal excitability. Disrupting this pathway resulted in decreased NaVs expression, neuronal hypoexcitability, and other neurodevelopmental defects in somatosensory DRG neurons. Furthermore, PGE2 was not only implicated as a signaling molecule in this pathway but was also shown to play a crucial role in supporting neuronal maturation and normal sensory function. The findings highlight the necessity of active signaling from glial cells for developing sensory neurons to become fully excitable, revealing that glial cells can indirectly modulate neuronal excitability.
In conclusion, this study aims to broaden the current understanding of excitability. Researchers targeted to find a connection between Schwann cells and excitability, and they found out the effects of PGE 2 on excitability. These discoveries shed light on the complexities of excitability and offer promising insights for future research on treating disorders associated with excitability dysfunction.
Reference: Kantarci, H., Elvira, P. D., Thottumkara, A. P., O’Connell, E. M., Iyer, M., Donovan, L. J., Dugan, M. Q., Ambiel, N., Granados, A., Zeng, H., Saw, N. L., Brosius Lutz, A., Sloan, S. A., Gray, E. E., Tran, K. V., Vichare, A., Yeh, A. K., Münch, A. E., Huber, M., … Zuchero, J. B. (2024). Schwann cell-secreted PGE2 promotes sensory neuron excitability during development. Cell, 187(17), 4690-4712.e30. https://doi.org/10.1016/j.cell.2024.07.033
Author: Fatma Beyza Şahin
Editor: Fatma Duran
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