Neuroprotection by the NR3A Subunit of the NMDA Receptor

Abstract

Hyperactivation of NMDA-type glutamate receptors (NMDARs) results in excitotoxicity, contributing to damage in stroke and neurodegenerative disorders. NMDARs are generally comprised of NR1/NR2 subunits but may contain modulatory NR3 subunits. Inclusion of NR3 subunits reduces the amplitude and dramatically decreases the Ca 2ϩ permeability of NMDAR-associated channels in heterologous expression systems and in transgenic mice. Since excessive Ca 2ϩ influx into neurons is a crucial step for excitotoxicity, we asked whether NR3A subunits are neuroprotective. To address this question, we subjected neurons genetically lacking NR3A to various forms of excitotoxic insult. We found that cultured neurons prepared from NR3A knock-out (KO) mice displayed greater sensitivity to damage by NMDA application than wild-type (WT) neurons. In vivo, neonatal, but not adult, WT mice contain NR3A in the cortex, and neonatal NR3A KO mice manifested more damage than WT after hypoxia-ischemia. In adult retina, one location where high levels of NR3A normally persist into adulthood, injection of NMDA into the eye killed more retinal ganglion cells in adult NR3A KO than WT mice. These data suggest that endogenous NR3A is neuroprotective. We next asked whether we could decrease excitotoxicity by overexpressing NR3A. We found that cultured neurons expressing transgenic (TG) NR3A displayed greater resistance to NMDA-mediated neurotoxicity than WT neurons. Similarly in vivo, adult NR3A TG mice subjected to focal cerebral ischemia manifested less damage than WT mice. These data suggest that endogenous NR3A protects neurons, and exogenously added NR3A increases neuroprotection and could be potentially exploited as a therapeutic.

A Mechanism Study of NMDAR1 in A Rat Alzheimer Disease (AD) Model

“…There are two major subtypes of NMDAR including the functional subtype NMDAR1, and the regulatory subtype NMDAR2. Studies have found that NMDAR can regulate the synaptic growth, development and plasticity through changing the ratio of NMDAR1/NMDAR2, NO-mediated enzyme and the ion channel [15,16], and ultimately regulate signal transmission between synapses. Therefore, studies on NMDAR1 expression might provide insights into the role of NMDAR1 in the pathogenesis of AD.…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…GluN3A is expressed primarily in early postnatal life, whereas GluN3B is found in adult brainstem and spinal cord (Petralia and Wenthold, 2008). GluN3A expression seems to be a critical step in synaptogenesis and spine formation, and it maintains receptors in an immature state (Pérez-Otañ o et al, 2006), perhaps with enhanced neuroprotection (Nakanishi et al, 2009). Subsequent down-regulation of GluN3A expression is important for synapse maturation and the emergence of a competent state for synaptic plasticity (Roberts et al, 2009).…”

Recalculation of 23 mouse HDL QTL datasets improves accuracy and allows for better candidate gene analysis

“…Traditional NMDA receptors are key players in glutamate-facilitated neurotransmission ( 24 ). Studies have suggested that expression of Grin3a is highest in selected regions of the brain in the postnatal period and in the adult retina, where the GRIN3A/NR3A subunit is thought to inhibit NMDA receptor Ca 2+ permeability and has a neuroprotective function ( 25 ). Similarly, expression of Grin3a is high in the neonatal kidney, but expression does persist into adulthood.…”