Physiological functions of D-serine mediated through δ2 glutamate receptors in the cerebellum

D-Serine (D-Ser), a major gliotransmitter, acts as an endogenous co-agonist for the N-methyl-D-aspartate-type ionotropic glutamate receptor (NMDA receptor) which regulates synaptic plasticity underlying certain types of learning and memory in the central nervous system. While D-Ser is abundant in the forebrain throughout life, it exists only transiently in the immature cerebellum because D-amino acid oxidase (DAAO), a D-Ser-degrading enzyme, begins to be highly expressed in the mature cerebellum. However, it remains unclear why and how D-Ser impacts physiological functions in the developing cerebellum. Recently, D-Ser has been reported to bind to δ2-type ionotropic glutamate receptors (δ2 receptors), which are exclusively expressed on the excitatory synapses between cerebellar granule cell axons (parallel fibers) and Purkinje cells, and control the induction of long-term depression (LTD), a form of synaptic plasticity underlying cerebellar motor learning. In the developing cerebellum, we found that D-Ser, released from Bergmann glia in response to neuronal activity, binds to δ2 receptors, thereby conveying a critical signal for LTD and motor learning. Interestingly, while D-Ser activates NMDA receptor-coupled channels, it evoked non-channel functions of δ2 receptors. In addition to δ2 receptors, their homolog δ1 receptors are widely expressed in various brain regions throughout life and also bind to D-Ser; therefore, D-Ser-δ receptor interactions may be a general signaling mechanism by which glia communicate with neurons, an important facet of the tripartite synapse.