A network model of the modulation of gamma oscillations by NMDA receptors in cerebral cortex

Psychotic drugs such as ketamine induce symptoms close to schizophrenia, and stimulate the production of gamma oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating gamma oscillations, and have integrated the action of drugs such as ketamine to partially block n-methyl-d-Aspartate (NMDA) receptors. The model can reproduce the paradoxical increase of gamma oscillations by NMDA-receptor antagonists, assuming that antagonists affect NMDA receptors with higher affinity on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channnels are diminished, an increase of gamma power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to gamma states, but was also present in asynchronous states with no apparent gamma. We conclude that NMDA antagonists induce an increased excitability state, which may or may not produce gamma oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations. Significance Statement n-methyl-d-Aspartate (NMDA) synaptic receptors mediate excitatory interactions using the neurotransmitter glutamate. NMDA receptors have been implicated in psychosis such as schizophrenia and are also targeted by hallucinogenic drugs like Ketamine. However, the exact mechanisms of action are sill unclear. Furthermore, Ketamine paradoxially leads to and excited state, while it is a blocker of NMDA receptors, therefore in principle diminishing excitation. Here, we use models of cortical networks generating gamma oscillations, and show that this model can explain the paradoxical exciting effect of Ketamine if one assumes a higher affinity on NMDA receptors of inhibitory interneurons. The simulated Ketamine effect reproduces known symptoms of psychosis such as increased gamma oscillations and exacerbated responses to external inputs, compatible with hallucinations.