Physiological roles of D-serine in the central nervous system

Abstract

The N-methyl D-aspartic acid receptors (NMDARs) are key glutamate receptors that transduce glutamatergic signals throughout the developing and adult central nervous system (CNS). Despite diversity in their subunit composition, their subcellular localization, and their biophysical and pharmacological properties, activation of NMDARs always requires in addition to glutamate the binding of a co-agonist that has long been thought to be glycine. However, research over the last two decades has challenged this long-cherished model by showing that the D-isomer of serine is the preferential co-agonist for a large population of NMDARs in many areas of the adult brain. Nowadays, a totally new picture of glutamatergic synapses is emerging where both glycine and D-serine are involved in a complex interplay to regulate NMDAR functions in the CNS following time and space constraints. In this review, we focus on the particular contribution of D-serine relatively to glycine in orchestrating synapse formation, dynamics, and neuronal network activity in a time- and synapse-specific manner and its role in cognitive functions. We will discuss also how astroglia and neurons use different pathways to regulate levels of extracellular D-serine and how alterations in synaptic availability of this D-amino acid may contribute to cognitive deficits associated to healthy aging and therefore may open new avenues for therapies.