GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain.

Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses.

GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia.

Background: Parvalbumin interneuron (PVI) activity synchronizes the medial prefrontal cortex circuit for normal cognitive function, and its impairment may contribute to schizophrenia (SZ). NMDA receptors in PVIs participate in these activities and form the basis for the NMDA receptor hypofunction hypothesis of SZ. However, the role of the GluN2D subunit, which is enriched in PVIs, in regulating molecular networks relevant to SZ is unknown.

Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.

The glutamate delta family of receptors is composed of GluD1 and GluD2 and serve as synaptic organizers. We have previously demonstrated several autism-like molecular and behavioral phenotypes including an increase in dendritic spines in GluD1 knockout mice. Based on previous reports we evaluated whether disruption of autophagy mechanisms may account for these phenotypes.

Dysfunction of Glutamate Delta-1 Receptor-Cerebellin 1 Trans-Synaptic Signaling in the Central Amygdala in Chronic Pain.

Chronic pain is a debilitating condition involving neuronal dysfunction, but the synaptic mechanisms underlying the persistence of pain are still poorly understood. We found that the synaptic organizer glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachio-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ) neurons. Deletion of GluD1 impairs excitatory neurotransmission at the PB-CeLC synapses.

Glutamate Delta-1 Receptor Regulates Inhibitory Neurotransmission in the Nucleus Accumbens Core and Anxiety-Like Behaviors.

Glutamate delta-1 receptor (GluD1) is a member of the ionotropic glutamate receptor family expressed at excitatory synapses and functions as a synaptogenic protein by interacting with presynaptic neurexin. We have previously shown that GluD1 plays a role in the maintenance of excitatory synapses in a region-specific manner. Loss of GluD1 leads to reduced excitatory neurotransmission in medium spiny neurons (MSNs) in the dorsal striatum, but not in the ventral striatum (both core and shell of the nucleus accumbens (NAc)).

Ultrastructural localization of glutamate delta 1 (GluD1) receptor immunoreactivity in the mouse and monkey striatum.

The glutamate receptor delta 1 (GluD1) is strongly expressed in the striatum. Knockout of GluD1 expression in striatal neurons elicits cognitive deficits and disrupts the thalamostriatal system in mice. To understand the potential role of GluD1 in the primate striatum, we compared the cellular and subcellular localization of striatal GluD1 immunoreactivity (GluD1-IR) in mice and monkeys.

Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity.

Impaired behavioral flexibility and repetitive behavior is a common phenotype in autism and other neuropsychiatric disorders, but the underlying synaptic mechanisms are poorly understood. The trans-synaptic glutamate delta (GluD)-Cerebellin 1-Neurexin complex, critical for synapse formation/maintenance, represents a vulnerable axis for neuropsychiatric diseases. We have previously found that GluD1 deletion results in reversal learning deficit and repetitive behavior.

Differential effect of NMDA receptor GluN2C and GluN2D subunit ablation on behavior and channel blocker-induced schizophrenia phenotypes.

The GluN2C- and GluN2D-containing NMDA receptors are distinct from GluN2A- and GluN2B-containing receptors in many aspects including lower sensitivity to Mg block and lack of desensitization. Recent studies have highlighted the unique contribution of GluN2C and GluN2D subunits in various aspects of neuronal and circuit function and behavior, however a direct comparison of the effect of ablation of these subunits in mice on pure background strain has not been conducted. Using knockout-first strains for the GRIN2C and GRIN2D produced on pure C57BL/6N strain, we compared the effect of partial or complete ablation of GluN2C and GluN2D subunit on various behaviors relevant to mental disorders.

Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens.

Cocaine exposure induces plasticity of glutamatergic synapses of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), which has been proposed to contribute to its addictive behavior. The mechanisms underlying cocaine-induced plasticity are not fully understood. The orphan glutamate delta-1 (GluD1) receptor is a member of the ionotropic glutamate receptor family but does not function as a typical ligand-gated ion channel.

Region-specific Expression of NMDA Receptor GluN2C Subunit in Parvalbumin-Positive Neurons and Astrocytes: Analysis of GluN2C Expression using a Novel Reporter Model.

Hypofunction of NMDA receptors in parvalbumin (PV)-positive interneurons has been proposed as a potential mechanism for cortical abnormalities and symptoms in schizophrenia. GluN2C-containing receptors have been linked to this hypothesis due to the higher affinity of psychotomimetic doses of ketamine for GluN1/2C receptors. However, the precise cell-type expression of GluN2C subunit remains unknown.

The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function.

Despite strong evidence for NMDA receptor (NMDAR) hypofunction as an underlying factor for cognitive disorders, the precise roles of various NMDAR subtypes remains unknown. The GluN2C-containing NMDARs exhibit unique biophysical properties and expression pattern, and lower expression of GluN2C subunit has been reported in postmortem brains from schizophrenia patients. We found that loss of GluN2C subunit leads to a shift in cortical excitatory-inhibitory balance towards greater inhibition.

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.

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.

Deletion of glutamate delta-1 receptor in mouse leads to enhanced working memory and deficit in fear conditioning.

Glutamate delta-1 (GluD1) receptors are expressed throughout the forebrain during development with high levels in the hippocampus during adulthood. We have recently shown that deletion of GluD1 receptor results in aberrant emotional and social behaviors such as hyperaggression and depression-like behaviors and social interaction deficits. Additionally, abnormal expression of synaptic proteins was observed in amygdala and prefrontal cortex of GluD1 knockout mice (GluD1 KO).