Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Physiology

Background:

• N-methyl-d-aspartate receptors (NMDARs) are crucial for neuronal function, existing at synaptic and extrasynaptic sites.
• The specific coagonists and their roles in NMDAR activation remain incompletely understood.

Purpose of the Study:

• To identify the distinct endogenous coagonists for synaptic and extrasynaptic NMDARs.
• To elucidate the functional implications of coagonist segregation on NMDAR activity and brain processes.

Main Methods:

• Investigated coagonist binding affinities for synaptic versus extrasynaptic NMDARs.
• Analyzed the effects of d-serine and glycine on NMDAR surface trafficking.
• Examined the roles of distinct NMDAR populations in long-term potentiation, long-term depression, and neurotoxicity.

Main Results:

• Synaptic NMDARs are preferentially activated by d-serine, while extrasynaptic NMDARs utilize glycine.
• Both coagonists modulate NMDAR surface trafficking in a subunit-dependent manner.
• Synaptic NMDARs mediate long-term potentiation and NMDA-induced neurotoxicity, whereas long-term depression involves both receptor populations.

Conclusions:

• NMDAR function is critically dependent on the specific coagonist and receptor location.
• This segregation provides novel insights into the distinct physiological and pathological roles of synaptic and extrasynaptic NMDARs in brain function.