Glutamate Delta 1 Receptor in Synapses, Circuits, and Disease

The glutamate delta 1 receptor (GluD1) remained largely unexplored since its cloning three decades ago because it lacked typical ligand-gated ion channel activity. In the last decade, much progress has been made in identifying its potential function. This research has been greatly enhanced by the development of specific tools to determine receptor expression and distribution and genetic mouse models to explore region specific roles in regulating circuits and behavior. Major strides have also been taken in understanding the structure-function of the receptor. These studies demonstrate that GluD1 has many distinctive characteristics including synaptogenic activity at both excitatory and inhibitory synapses, the ability of the ligand-binding domain to bind not only D-serine but also GABA, its unique structural arrangement among the ionotropic glutamate receptor family in relation to domain swapping and the ability to induce tonic currents in the native system. Studies have also identified its role in regulating the postsynaptic content of AMPA and NMDA receptors and synaptic plasticity. Finally, human genetic studies revealed the relationship of GluD1 with neuropsychiatric disorders, including schizoaffective disorders and intellectual disability, which is consistent with the phenotypes observed in mice upon GluD1 ablation. The role of GluD1 is also becoming evident in neurological disorders, particularly chronic pain. Thus, GluD1 has quickly emerged as a receptor with multifaceted roles in physiology and pathology.