An emerging map of glutamate delta 1 receptors in the forebrain

Abstract

Glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) form the delta family of ionotropic glutamate receptors; these proteins plays widespread roles in synaptic architecture, motor behavior, and cognitive function. Though the role of GluD2 at cerebellar parallel fiber-Purkinje cell synapses is well established, attention now turns to the function of GluD receptors in the forebrain. GluD1 regulates synaptic assembly and modulation in multiple higher brain regions, acting as a postsynaptic cell adhesion molecule with effects on both excitatory and inhibitory transmission. Furthermore, variations and mutations in the GRID1 gene, which codes for GluD1, and in genes which code for proteins functionally linked to GluD1, are associated with mental disorders including autism, schizophrenia, bipolar disorder, and major depression. Cerebellin (Cbln) family proteins, the primary binding partners of delta receptors, are secreted C1q-like proteins which also bind presynaptic neurexins (NRXNs), forming a tripartite synaptic bridge. Published research explores this bridge's function in regions including the striatum, hippocampus, cortex, and cerebellum. In this review, we summarize region- and circuit-specific functions and expression patterns for GluD1 and its related proteins, and their implications for behavior and disease.

Figure 1.

The tripartite synaptic bridge is composed of; (i) AS4-positive NRXN anchored in the presynaptic membrane, (ii) Secreted Cbln hexamers joining the presynaptic (NRXN) and postsynaptic (GluD) bridge components, and (iii) a GluD receptor binding Cbln at its amino terminal domain (ATD).

Figure 2:

Schematic showing GluD and Cbln1 function in cerebellum. Cbln1 secreted from parallel fibers synaptogenically engages with GluD1 expressed on cerebellar interneurons and GluD2 expressed on Purkinje cell dendrites.

Figure 3:

Schematic illustrating proposed GluD and Cbln involvement in the dorsal and ventral striatum. (a) Cbln2 is present in cortico-striatal projections, but its postsynaptic target and function are not known. (b) Cbln1 is secreted by afferents from the parafascicular thalamus and synapses with GluD1 expressed on the dendrites of striatal medium spiny neurons (MSNs). (c) Cbln1 is produced in glutamatergic neurons in the VTA and affects excitatory transmission in the NAc, though its postsynaptic target is not confirmed.