The t-N-methyl-d-aspartate receptor: Making the case for d-Serine to be considered its inverse co-agonist

The N-methyl-d-aspartate receptor (NMDAR) is an enigmatic macromolecule that has garnered a good deal of attention on account of its involvement in the cellular processes that underlie learning and memory, following its discovery in the mid twentieth century (Baudry and Davis, 1991). Yet, despite advances in knowledge about its function, there remains much more to be uncovered regarding the receptor's biophysical properties, subunit composition, and role in CNS physiology and pathophysiology. The motivation for this review stems from the need for synthesizing new information gathered about these receptors that sheds light on their role in synaptic plasticity and their dichotomous relationship with the amino acid d-serine through which they influence the pathogenesis of neurodegenerative diseases like temporal lobe epilepsy (TLE), the most common type of adult epilepsies (Beesley et al., 2020a). This review will outline pertinent ideas relating structure and function of t-NMDARs (GluN3 subunit-containing triheteromeric NMDARs) for which d-serine might serve as an inverse co-agonist. We will explore how tracing d-serine's origins blends glutamate-receptor biology with glial biology to help provide fresh perspectives on how neurodegeneration might interlink with neuroinflammation to initiate and perpetuate the disease state. Taken together, we envisage the review to deepen our understanding of endogenous d-serine's new role in the brain while also recognizing its therapeutic potential in the treatment of TLE that is oftentimes refractory to medications.