Synaptic NMDA Receptors Mediate Hypoxic Excitotoxic Death

Abstract

Excessive NMDA receptor activation and excitotoxicity underlies pathology in many neuropsychiatric and neurological disorders, including hypoxia/ischemia. Thus, the development of effective therapeutics for these disorders demands a complete understanding of NMDA receptor (NMDAR) activation during excitotoxic insults. The extrasynaptic NMDAR hypothesis posits that synaptic NMDARs are neurotrophic/neuroprotective and extrasynaptic NMDARs are neurotoxic. In part, the extrasynaptic hypothesis is built on observed selectivity for extrasynaptic receptors of a neuroprotective use-dependent NMDAR channel blocker, memantine. In rat hippocampal neurons we found that a neuroprotective concentration of memantine shows little selectivity for extrasynaptic NMDARs when all receptors are tonically activated by exogenous glutamate. This led us to test the extrasynaptic NMDAR hypothesis using metabolic challenge, where the source of excitotoxic glutamate buildup may be largely synaptic. Three independent approaches suggest strongly that synaptic receptors participate prominently in hypoxic excitotoxicity. First, block of glutamate transporters with a non-substrate antagonist exacerbated rather than prevented damage, consistent with a primarily synaptic source of glutamate. Second, selective, preblock of synaptic NMDARs with a slowly reversible, use-dependent antagonist protected nearly fully against prolonged hypoxic insult. Third, glutamate pyruvate transaminase (GPT), which degrades ambient but not synaptic glutamate, did not protect against hypoxia but protected against exogenous glutamate damage. Together, these results suggest that synaptic NMDARs can mediate excitotoxicity, particularly when the glutamate source is synaptic and when synaptic receptor contributions are rigorously defined. Moreover, the results suggest that in some situations therapeutically targeting extrasynaptic receptors may be inappropriate.

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

“…3-8, but see ref. 9). Soluble oligomers of Aβ are thought to underlie dementia, mimic extracellular glutamate stimulation of eNMDARs, and disrupt synaptic plasticity and long-term potentiation, eventually leading to synaptic loss (1,6,10,11).…”

Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5–Nrf2 pathway

“…[23][24][25] Likewise, we show that Nr1a, Nr2a and Nr2b mRNA (Supplementary Figure 1m) and Nr2a and Nr2b protein (Supplementary Figure 1n) are expressed in astrocytes under our circumstances. As from 50 μM, NMDA is considered neurotoxic, 5,26 we used 20 μM NMDA thereafter as it triggered a similar [Ca permeability of NMDAR in astrocytes, as previously described. 27 Furthermore, incubation of astrocytes with NMDA (20 μM) in the absence of extracellular Ca 2+ ([Ca 2+ ] e.c.…”

Organization, control and function of extrasynaptic NMDA receptors

“…The idea that excitotoxicity may not be caused solely by extrasynaptic receptors is fuelled by recent and thorough insights into the mechanism of the use-dependent NMDAR blocker memantine [114,124]. Memantine was proposed to preferentially block extrasynaptic receptors over synaptic ones, owing to its fast off-rate, low affinity, voltage-dependent binding and uncompetitive nature [23,114,125]. The fact that memantine can successfully prevent neuronal death in vitro or in pathological conditions [23,126,127] has thus strongly contributed to the extrasynaptic hypothesis of excitotoxicity.…”