Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders

Abstract

NMDA receptor (NMDAR)-induced excitotoxicity is thought to contribute to the cell death associated with certain neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. Targeting NMDARs therapeutically is complicated by the fact that cell signaling downstream of their activation can promote cell survival and plasticity as well as excitotoxicity. However, research over the past decade has suggested that overactivation of NMDARs located outside of the synapse plays a major role in NMDAR toxicity, whereas physiological activation of those inside the synapse can contribute to cell survival, raising the possibility of therapeutic intervention based on NMDAR subcellular localization. Here, we review the evidence both supporting and refuting this localization hypothesis of NMDAR function and discuss the role of NMDAR localization in disorders of the nervous system. Preventing excessive extrasynaptic NMDAR activation may provide therapeutic benefit, particularly in Alzheimer disease and Huntington disease.

Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression

“…Ketamine is an open-channel NMDA receptor blocker, and is therefore theoretically more selective for extrasynaptic NMDA receptors, since these spend longer in the 'open' configuration because of a more tonic activation by extrasynaptic glutamate. Extrasynaptic NMDA receptors are known to induce long-term depression and are linked to neuronal inefficiency mechanisms (30)(31)(32), and their selective antagonism can be expected to increase neuronal activity. Indeed, it has been shown that systemically injected ketamine induces an acute (within 20 min) increase in extracellular glutamate levels in the frontal cortex of rats (33), which may be an indication of increased glutamate overflow from synapses due to enhanced neuronal firing.…”

Higher levels of phosphorylated Y1472 on GluN2B subunits in the frontal cortex of aged mice are associated with good spatial reference memory, but not cognitive flexibility

“…PSD-95 is normally enriched on synaptic membranes, but it can also be found on extrasynaptic membranes in the mouse model of Huntington's disease (Fan et al 2012;Zheng et al 2011). GluN2B-containing NMDArs are very mobile, moving easily between synaptic and extrasynaptic membranes (Groc et al 2006;Parsons and Raymond 2014). We hypothesized that there may be an aging effect on the membrane localization of NMDArs and their effector proteins.…”

PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP 61

“…In fact, GluN2B is the most prominent tyrosine phosphorylated protein within postsynaptic densities (PSDs) (14), and phosphorylation is increased during long-term potentiation (LTP) in CA1 hippocampus (15). Moreover, tyrosine phosphorylation of GluN2B has been shown to increase in several pathological conditions, including ischemia and seizures (16)(17)(18)(19).Striatal-enriched protein tyrosine phosphatase (STEP, also known as "PTPN5") is a brain-specific protein phosphatase that is expressed in the striatum, hippocampus, and cortex (20, 21). The STEP family of protein tyrosine phosphatases includes both membrane-associated [striatal-enriched protein tyrosine phosphatase 61 (STEP 61 )] and cytosolic (STEP 46 ) variants that are generated by alternative splicing of a single gene (22-24).…”

“…In fact, GluN2B is the most prominent tyrosine phosphorylated protein within postsynaptic densities (PSDs) (14), and phosphorylation is increased during long-term potentiation (LTP) in CA1 hippocampus (15). Moreover, tyrosine phosphorylation of GluN2B has been shown to increase in several pathological conditions, including ischemia and seizures (16)(17)(18)(19).…”