The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor.

Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

The neurodegenerative disorder Huntington disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, resulting in loss of striatal and cortical neurons. Although, the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here, we demonstrate the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt), and neuronal survival. Synaptic NMDA receptor (NMDAR) activity induces mtHtt inclusions via a TCP1 ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases vulnerability of mtHtt-neurons to cell death by impairing a neuroprotective CREB—PGC-1α cascade and increasing the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic YAC128 HD mice with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine also blocks synaptic NMDAR activity, decreases neuronal inclusions, and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in HD.

Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here, we show that Snx27−/− mice exhibit severe neuronal deficits in the hippocampus and cortex. While Snx27+/− mice exhibit grossly normal neuroanatomy, we find defects in synaptic function, learning and memory, and a reduction in ionotropic glutamate receptors (NMDARs and AMPARs). SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduction of SNX27 and C/EBPβ in Down syndrome brains and identify C/EBPβ as a transcription factor for SNX27. Down syndrome causes over-expression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 and resulting in synaptic dysfunction. Up-regulating SNX27 in the hippocampus of Down syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a novel molecular mechanism of Down syndrome pathogenesis.

Glutamate is the major excitatory neurotransmitter in the brain. The NMDA subtype of glutamate receptors (NMDAR) is known to mediate many physiological neural functions. However, excessive activation of NMDARs contributes to neuronal damage in various acute and chronic neurological disorders. To avoid unwanted adverse side effects, blockade of excessive NMDAR activity must therefore be achieved without affecting its physiological function. Memantine, an adamantane derivative, has been used for the treatment of Alzheimer's disease with an excellent clinical safety profile. We previously showed that memantine preferentially blocked neurotoxicity mediated by excessive NMDAR activity while relatively sparing normal neurotransmission, in part because of its uncompetitive antagonism with a fast off-rate. Here, using rat autaptic hippocampal microcultures, we show that memantine at therapeutic concentrations (1-10 M) preferentially blocks extrasynaptic rather than synaptic currents mediated by NMDARs in the same neuron. We found that memantine blocks extrasynaptic NMDAR-mediated currents induced by bath application of 100 M NMDA/10 M glycine with a twofold higher potency than its blockade of the NMDAR component of evoked EPSCs (EPSCs NMDAR ); this effect persists under conditions of pathological depolarization in the presence of 1 mM extracellular Mg 2ϩ . Thus, our findings provide the first unequivocal evidence to explain the tolerability of memantine based on differential extrasynaptic/synaptic receptor blockade. At therapeutic concentrations, memantine effectively blocks excessive extrasynaptic NMDAR-mediated currents, while relatively sparing normal synaptic activity.