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NMDA receptors in clinical neurology: excitatory times ahead.

ABSTRACT: Since the N-methyl-D-aspartate receptor (NMDAR) subunits were cloned less than two decades ago, a substantial amount of research has been invested into understanding their physiological function in the healthy CNS. Research has also been directed at their pathological roles in various neurological diseases, including disorders resulting from acute excitotoxic insults (eg, ischaemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (eg, Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis), disorders arising from sensitisation of neurons (eg, epilepsy, neuropathic pain), and neurodevelopmental disorders associated with NMDAR hypofunction (eg, schizophrenia). Selective NMDAR antagonists have not produced positive results in clinical trials. However, there are other NMDAR-targeted therapies used in current practice that are effective for treating some neurological disorders. In this Review, we describe the evidence for the use of these therapies and provide an overview of drugs being investigated in clinical trials. We also discuss new NMDAR-targeted strategies in clinical neurology.

SUBMITTER: Kalia LV

PROVIDER: S-EPMC3589564 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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NMDA receptors in clinical neurology: excitatory times ahead.

Kalia Lorraine V LV Kalia Suneil K SK Salter Michael W MW

The Lancet. Neurology 20080801 8

Since the N-methyl-D-aspartate receptor (NMDAR) subunits were cloned less than two decades ago, a substantial amount of research has been invested into understanding their physiological function in the healthy CNS. Research has also been directed at their pathological roles in various neurological diseases, including disorders resulting from acute excitotoxic insults (eg, ischaemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (eg, Alzheimer's, Parkinson's, and Hunti ...[more]

PMID: 18635022

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Project description:Excitatory signaling mediated by NMDARs has been shown to regulate mood disorders. However, current treatments targeting NMDAR subtypes have shown limited success in treating patients, highlighting a need for alternative therapeutic targets. Here, we identify a role for GluN2D-containing NMDARs in modulating emotional behaviors and neural activity in the bed nucleus of the stria terminalis (BNST). Using a GluN2D KO mouse line (GluN2D-/-), we assessed behavioral phenotypes across tasks modeling emotional behavior. We then used a combination of ex vivo electrophysiology and in vivo fiber photometry to assess changes in BNST plasticity, cell-specific physiology, and cellular activity profiles. GluN2D-/- male mice exhibit evidence of exacerbated negative emotional behavior, and a deficit in BNST synaptic potentiation. We also found that GluN2D is functionally expressed on corticotropin-releasing factor (CRF)-positive BNST cells implicated in driving negative emotional states, and recordings in mice of both sexes revealed increased excitatory and reduced inhibitory drive onto GluN2D-/- BNST-CRF cells ex vivo and increased activity in vivo Using a GluN2D conditional KO line (GluN2Dflx/flx) to selectively delete the subunit from the BNST, we find that BNST-GluN2Dflx/flx male mice exhibit increased depressive-like behaviors, as well as altered NMDAR function and increased excitatory drive onto BNST-CRF neurons. Together, this study supports a role for GluN2D-NMDARs in regulating emotional behavior through their influence on excitatory signaling in a region-specific manner, and suggests that these NMDARs may serve as a novel target for selectively modulating glutamate signaling in stress-responsive structures and cell populations.SIGNIFICANCE STATEMENT Excitatory signaling mediated through NMDARs plays an important role in shaping emotional behavior; however, the receptor subtypes/brain regions through which this occurs are poorly understood. Here, we demonstrate that loss of GluN2D-containing NMDARs produces an increase in anxiety- and depressive-like behaviors in mice, deficits in BNST synaptic potentiation, and increased activity in BNST-CRF neurons known to drive negative emotional behavior. Further, we determine that deleting GluN2D in the BNST leads to increased depressive-like behaviors and increased excitatory drive onto BNST-CRF cells. Collectively, these results demonstrate a role for GluN2D-NMDARs in regulating the activity of stress-responsive structures and neuronal populations in the adult brain, suggesting them as a potential target for treating negative emotional states in mood-related disorders.

Dataset Information

NMDA receptors in clinical neurology: excitatory times ahead.

Publications

NMDA receptors in clinical neurology: excitatory times ahead.

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