How could N-Methyl-D-Aspartate Receptor Antagonists Lead to Excitation Instead of Inhibition?

N-methyl-D-aspartate receptors (NMDARs) are a family of ionotropic glutamate receptors mainly known to mediate excitatory synaptic transmission and plasticity. Interestingly, low-dose NMDAR antagonists lead to increased, instead of decreased, functional connectivity; and they could cause schizophrenia- and/or antidepressant-like behavior in both humans and rodents. In addition, human genetic evidences indicate that NMDAR loss of function mutations underlie certain forms of epilepsy, a disease featured with abnormal brain hyperactivity. Together, they all suggest that under certain conditions, NMDAR activation actually lead to inhibition, but not excitation, of the global neuronal network. Apparently, these phenomena are rather counterintuitive to the receptor's basic role in mediating excitatory synaptic transmission. How could it happen? Recently, this has become a crucial question in order to fully understand the complexity of NMDAR function, particularly in disease. Over the past decades, different theories have been proposed to address this question. These include theories of “NMDARs on inhibitory neurons are more sensitive to antagonism”, or “basal NMDAR activity actually inhibits excitatory synapse”, etc. Our review summarizes these efforts, and also provides an introduction of NMDARs, inhibitory neurons, and their relationships with the related diseases. Advances in the development of novel NMDAR pharmacological tools, particularly positive allosteric modulators, are also included to provide insights into potential intervention strategies.