Spatial Coupling Tunes NMDA Receptor Responses via Ca²⁺Diffusion

Abstract

In the CNS, NMDA receptors generate large and highly regulated Ca 2ϩ signals, which are critical for synaptic development and plasticity. They are highly clustered at postsynaptic sites and along dendritic arbors, but whether this spatial arrangement affects their output is unknown. Synaptic NMDA receptor currents are subject to Ca 2ϩ-dependent inactivation (CDI), a type of activity-dependent inhibition that requires intracellular Ca 2ϩ and calmodulin (CaM). We asked whether Ca 2ϩ influx through a single NMDA receptor influences the activity of nearby NMDA receptors, as a possible coupling mechanism. Using cell-attached unitary current recordings from GluN1-2a/ GluN2A receptors expressed in human HEK293 cells and from NMDA receptors native to hippocampal neurons from male and female rats, we recorded unitary currents from multichannel patches and used a coupled Markov model to determine the extent of signal coupling (). In the absence of extracellular Ca 2ϩ , we observed no cooperativity (Ͻ 0.1), whereas in 1.8 mM external Ca 2ϩ , both recombinant and native channels showed substantial negative cooperativity (ϭ 0.27). Intracellular Ca 2ϩ chelation or overexpression of a Ca 2ϩ-insensitive CaM mutant, reduced coupling, which is consistent with CDI representing the coupling mechanism. In contrast, cooperativity increased substantially (ϭ 0.68) when overexpressing the postsynaptic scaffolding protein PSD-95, which increased receptor clustering. Together, these new results demonstrate that NMDA receptor currents are negatively coupled through CDI, and the degree of coupling can be tuned by the distance between receptors. Therefore, channel clustering can influence the activity-dependent reduction in NMDA receptor currents.

Distance-dependent regulation of NMDAR nanoscale organization along hippocampal neuron dendrites

“…Could changes in receptor distribution and local density within nanodomains affect NMDAR-mediated transmission? Simulation studies seem to indicate that NMDAR activation is not extensively impacted by their organization into nanodomains ( 68 ), yet NMDAR currents are negatively coupled through calcium-dependent inactivation, and the degree of coupling is tuned by the distance between receptors; that is, NMDARs in close proximity efficiently inhibit one another ( 69 ). Thus, NMDARs at distal synapses are theoretically more prone to calcium-dependent inactivation, particularly when trains of action potentials trigger large local increases in intracellular calcium, and this strong compaction of distal receptors may have important consequences on NMDAR signaling.…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…This can occur when calmodulin is close to the channel and senses Ca 21 arriving through the pore of the channel (Iacobucci and Popescu, 2017b). Moreover, Ca 21 entering one NMDA receptor can desensitize an adjacent receptor, providing a mechanism for negative coupling, and this effect is enhanced by PSD-95 clustering (Iacobucci and Popescu, 2019).…”

Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus

“…When glutamate receptors are excessively activated, it results in an acute rise in intracellular calcium levels and causes excitotoxicity. Effective inhibition of NMDA receptors may be a potential therapeutic strategy for tinnitus [ 15 ]. Once the neurons are stressed due to chronic glutamate excitotoxicity, they eventually undergo cell death [ 16 ].…”

“…The elevated levels of NMDA receptor due to administration of high doses of salicylate increases intracellular Ca 2+ influx and induces excitotoxicity [ 15 , 27 ]. Neuronal hyperactivity by NMDA receptors could also stimulate plasticity signals, such as CREB phosphorylation [ 12 , 28 ].…”