Enriched Expression of GluD1 in Higher Brain Regions and Its Involvement in Parallel Fiber–Interneuron Synapse Formation in the Cerebellum

Abstract

Of the two members of the ␦ subfamily of ionotropic glutamate receptors, GluD2 is exclusively expressed at parallel fiber-Purkinje cell (PF-PC) synapses in the cerebellum and regulates their structural and functional connectivity. However, little is known to date regarding cellular and synaptic expression of GluD1 and its role in synaptic circuit formation. In the present study, we investigated this issue by producing specific and sensitive histochemical probes for GluD1 and analyzing cerebellar synaptic circuits in GluD1-knock-out mice. GluD1 was widely expressed in the adult mouse brain, with high levels in higher brain regions, including the cerebral cortex, striatum, limbic regions (hippocampus, nucleus accumbens, lateral septum, bed nucleus stria terminalis, lateral habenula, and central nucleus of the amygdala), and cerebellar cortex. In the cerebellar cortex, GluD1 mRNA was expressed at the highest level in molecular layer interneurons and its immunoreactivity was concentrated at PF synapses on interneuron somata. In GluD1-knock-out mice, the density of PF synapses on interneuron somata was significantly reduced and the size and number of interneurons were significantly diminished. Therefore, GluD1 is common to GluD2 in expression at PF synapses, but distinct from GluD2 in neuronal expression in the cerebellar cortex; that is, GluD1 in interneurons and GluD2 in PCs. Furthermore, GluD1 regulates the connectivity of PF-interneuron synapses and promotes the differentiation and/or survival of molecular layer interneurons. These results suggest that GluD1 works in concert with GluD2 for the construction of cerebellar synaptic wiring through distinct neuronal and synaptic expressions and also their shared synapse-connecting function.

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…The general expression pattern of mGlu5 is very similar to that of GluD1, and at excitatory synapses, these two receptors appear to be located at the perisynaptic region (Lujan et al, 1996;Shigemoto and Mizuno, 2000;Hepp et al, 2014;Konno et al, 2014). These findings suggest possible direct or indirect interactions between mGlu5 and GluD1 proteins.…”

“…Recent studies demonstrate that GluD1 is enriched in the forebrain as well as the cerebellum during both early development and adulthood (Hepp et al, 2014;Konno et al, 2014). GluD1 is particularly abundant in the hippocampus, with high mRNA and protein expression in pyramidal neurons (Hepp et al, 2014).…”

“…in the hippocampus and striatum, regions where abundant expression of these receptors is observed (Shigemoto and Mizuno, 2000;Konno et al, 2014). Moreover, the mGlu5 interaction with scaffold protein Homer and downstream Akt-mTOR pathway is dysregulated in the absence of GluD1.…”

“…GluD1 is widely expressed in the brain, with high levels in the hippocampus (Lomeli et al, 1993;Yadav et al, 2012;Hepp et al, 2014;Konno et al, 2014;Gupta et al, 2015). Among the ionotropic glutamate receptors, delta receptors are unique in that they do not exhibit agonist-induced current in a heterologous expression system.…”

“…Recent expression studies demonstrated that the general pattern of GluD1 expression is quite similar to that of metabotropic glutamate receptor 5 (mGlu5)-in particular, they are predominantly expressed in the cortex, hippocampus, and striatum in the forebrain region (Shigemoto and Mizuno, 2000;Hepp et al, 2014;Konno et al, 2014). Moreover, at a subcellular level, GluD1 (similar to mGlu5) is localized postsynaptically at perisynaptic/extrasynaptic sites (Lujan et al, 1996;Hepp et al, 2014).…”