Rare amino acid demonstrates potential to reshape our understanding of brain communication and pain

A recent study from the Texas A&M University Health Science Center (Texas A&M Health) has uncovered a new role for D-serine—a rare, naturally occurring amino acid in mammals—in shaping how brain cells form connections and communicate. These findings have major implications for understanding and potentially harnessing synaptic plasticity in conditions like chronic pain and neurodegenerative disorders.

Synaptic plasticity, or how the networked cells in our brains change in response to experience, is a significant area of research for understanding both our own development and how our minds respond to signals such as pain. However, the precise mechanisms are diverse and still poorly understood.

“Understanding synaptic plasticity is crucial because it’s the brain’s way of adapting, learning and storing memories,” said Kishore Kumar S. Narasimhan, PhD, a postdoctoral researcher in the laboratory of Shashank M. Dravid, PhD, at the Texas A&M University College of Medicine. “In simple terms, synaptic plasticity refers to how connections between brain cells (neurons) strengthen or weaken based on experience. Furthermore, synaptic plasticity is the foundation of how we think, remember and adapt—it’s what makes us who we are.”

Dravid’s team investigated how D-serine influences neuronal communication. Their research, published in Cellular and Molecular Life Sciences, reveals that D-serine plays a surprising role in weakening neural connections, offering new insights into how synapses form and function.

For years, scientists have known D-serine plays a role in synaptic plasticity, brain development, and psychiatric and neurodegenerative disorders. It helps activate another set of molecules called NMDA (N-methyl-D-aspartate) receptors as one mechanism for altering synapses. A lesser-known cousin to NMDA receptors, the glutamate delta-1 (GluD1) receptor, is not as understood and could represent another way D-serine interacts with the brain. Interestingly, D-serine may act differently with GluD1 versus NMDA, and this distinction could mark another way D-serine alters neuron communication.

Dravid’s team focused particularly on the interaction between GluD1 and cerebellin-1 (or Cbln1), another protein that is essential for forming neural connections. Their experiments showed that while increased Cbln1 strengthened neural connections, the presence of D-serine significantly weakened these connections. Further, when compared with a modified GluD1 with reduced binding to D-serine, this weakening effect no longer occurred.

These findings suggest that in addition to D-serine’s known role as a co-activator for other receptors, it may also actively regulate how closely neuronal synapses can organize based on Glud1 and Cbln1 interactions. This discovery could prove crucial for understanding conditions in which neural plasticity is disrupted, such as chronic pain and neurodegenerative diseases.

“The study’s findings are clinically significant, especially in understanding the mechanisms underlying chronic pain and potential therapeutic strategies to manage it,” Narasimhan said. “Chronic pain often results from complex changes in neural circuits and synapses, and this research provides insight into one of the key processes involved in this dysfunction.”

Looking ahead, the research team plans to further investigate how D-serine influences learning and memory, as well as its role in human neurological disorders like schizophrenia. They also aim to explore whether therapies targeting or modulating D-serine could lead to new treatment for brain-related conditions.