Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity

Abstract

The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2Bcontaining receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders.

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

“…We have recently identified a critical role of GluD1 in the development of excitatory synapses in the hippocampus as well as the prefrontal cortex. Specifically, loss of GluD1 prevents the normal developmental pruning of dendritic spines and leads to a higher number of excitatory synapses in adulthood (Gupta et al, 2015). Loss of GluD1 also impairs the normal switch from GluN2B to GluN2A NMDA receptor subunit in the hippocampus and cortex (Gupta et al, 2015).…”

“…2B). This finding may be explained by potential disruption of normal activity-dependent modulation of mGlu5 scaffold in GluD1 KO (Gupta et al, 2015). For example, loss of GluD1 may impair upregulation of the short-form Homer in response to mGlu5 activation, which may thereby prevent the sequestration of mGlu5.…”

“…We also observed specific cognitive deficits in hippocampus-dependent contextual fear learning and reversal learning in GluD1 knockout (KO) mice (Yadav et al, 2012(Yadav et al, , 2013. More recently, we have found that loss of GluD1 produces molecular phenotypes relevant to autism and developmental delay, including impaired dendritic spine pruning and switch in N-methyl-D-aspartate (NMDA) receptor GluN2B to the GluN2A subunit in the hippocampus and prefrontal cortex (Grossman et al, 2006;Penzes et al, 2011;Swanger et al, 2011;Gupta et al, 2015). Indeed, singlenucleotide polymorphism and copy-number variation studies have identified the GRID1 gene, which codes for GluD1, as a susceptibility gene for autism, schizophrenia, bipolar disorder, and major depression (Fallin et al, 2005;Glessner et al, 2009;Smith et al, 2009;Greenwood et al, 2011;Nord et al, 2011;Edwards et al, 2012;Griswold et al, 2012).…”

“…However, GluN1 subunit ligands, such as D-serine and glycine, bind to the ligandbinding domain and induce conformational change in the GluD1 receptor (Naur et al, 2007;Yadav et al, 2011). We have recently shown that loss of GluD1 in a mouse model leads to abnormal social and emotional behaviors, including social interaction deficits and repetitive behavior (Yadav et al, 2012(Yadav et al, , 2013Gupta et al, 2015). We also observed specific cognitive deficits in hippocampus-dependent contextual fear learning and reversal learning in GluD1 knockout (KO) mice (Yadav et al, 2012(Yadav et al, , 2013.…”

“…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.…”