How a rare epilepsy-associated mutation disrupts neuronal communication



NMDA receptors in the brain serve several important functions, including stimulating neurons and guiding brain development. Rare genetic variations in NMDA receptors may impair their functioning and have been implicated in disorders of brain development, but how exactly these disease-associated mutations affect the receptors is poorly understood.


An IRP team led by postdoctoral fellow Marta Mota Vieira, Ph.D., examined how a rare mutation in a gene related to epilepsy affects NMDA receptors. The researchers discovered that the section of the NMDA receptor affected by the mutation is important for moving the receptor from the body of a nerve cell to the cell’s surface, where the receptors can interact with other cells. The mutation can also influence the way the NMDA receptor interacts with other proteins involved in communication between neurons. Furthermore, the researchers found that the mutation disrupted important molecular interactions and resulted in fewer NMDA receptors on cells, impaired signaling between nerve cells, and fewer specialized structures called spines that are important for communication between neurons. Finally, the study revealed an important and previously unappreciated relationship between part of the NMDA receptor subunit and an enzyme that is believed to be involved in learning- and memory-related processes in the brain.


This work sheds light on the molecular mechanisms involved in NMDA receptor regulation during brain development, as well as how NMDA receptors work both in the healthy brain and in neurological diseases. Moreover, the study represents an important early step in understanding the mechanisms by which rare genetic mutations affect different parts of the NMDA receptor and cause neurodevelopmental disorders. This knowledge may inform the development of future treatments for neurological diseases.


Mota Vieira M, Nguyen TA, Wu K, Badger JD 2nd, Collins BM, Anggono V, Lu W, Roche KW. (2020). An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking. Cell Rep. Sep 1;32(9):108104. doi: 10.1016/j.celrep.2020.108104.

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This page was last updated on Thursday, June 8, 2023