Excitatory neurotransmission in the vertebrate central nervous system is mainly mediated by ionotropic glutamate receptors (iGluRs). Molecular cloning identified 18 mammalian iGluR subunits, of which only 16 sort into the traditional pharmacological subfamilies of AMPA, kainate (KA), and N-methyl-D-aspartate (NMDA) receptors. The 2 remaining subunits were termed “orphan” receptors, “glutamate-like” receptors, “nonionotropic” receptors, or, most commonly, delta receptors¹.

Ionotropic glutamate receptors are integral membrane proteins composed of four large subunits that form a central ion channel pore. Sequence similarity among all known glutamate receptor subunits, including the δ receptors, suggests they share a similar architecture. Glutamate receptor subunits are modular structures that contain four discrete semiautonomous domains: the extracellular amino-terminal domain (ATD), the extracellular ligand-binding domain (LBD), the transmembrane domain (TMD), and an intracellular carboxyl-terminal domain (CTD)². 

The delta family of ionotropic glutamate receptors (iGluRs) consists of the glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors³. GluD1 is highly expressed in the inner hair cells of the organ of Corti⁴, diffusely expressed throughout the forebrain during development with high levels in the hippocampus during adulthood³. Deletion of GluD1 leads to a deficit in high frequency hearing in mice⁵. Genetic association studies have established the GRID1 gene, which codes for GluD1, is a strong candidate gene for schizophrenia, bipolar disorder, and major depressive disorder⁶. Copy number variation studies have also implicated GRID1 in autism spectrum disorder (ASD)⁷. In addition, GRID1 gene is localized to the 10q22–q23 genomic region which is a site for recurrent deletions associated with cognitive and behavioral abnormalities⁸.