Mechanism of carbachol-induced 40 Hz gamma oscillations and the effects of NMDA activation on oscillatory dynamics in a model of the CA3 subfield of the hippocampus.

Gamma oscillations are a prominent feature of various neural systems, including the CA3 subfield of the hippocampus. In CA3, in vitro carbachol application induces ∼40 Hz gamma oscillations in the network of glutamatergic excitatory pyramidal neurons (PNs) and local GABAergic inhibitory neurons (INs). Activation of NMDA receptors within CA3 leads to an increase in the frequency of carbachol-induced oscillations to ∼60 Hz, a broadening of the distribution of individual oscillation cycle frequencies, and a decrease in the time lag between PN and IN spike bursts. In this work, we develop a biophysical integrate-and-fire model of the CA3 subfield, we show that the dynamics of our model are in concordance with physiological observations, and we provide computational support for the hypothesis that the 'E-I' mechanism is responsible for the emergence of ∼40 Hz gamma oscillations in the absence of NMDA activation. We then incorporate NMDA receptors into our CA3 model, and we show that our model exhibits the increase in gamma oscillation frequency, broadening of the cycle frequency distribution, and decrease in the time lag between PN and IN spike bursts observed experimentally. Remarkably, we find an inverse relationship in our model between the net NMDA current delivered to PNs and INs in an oscillation cycle and cycle frequency. Furthermore, we find a disparate effect of NMDA receptors on PNs versus INs - we show that NMDA receptors on INs tend to increase oscillation frequency, while NMDA receptors on PNs tend to slightly decrease or not affect oscillation frequency. We find that these observations can be explained if NMDA activity above a threshold level causes a shift in the mechanism underlying gamma oscillations; in the absence of NMDA receptors, the 'E-I' mechanism is primarily responsible for the generation of gamma oscillations (at 40 Hz), while when NMDA receptors are active, the mechanism of gamma oscillations shifts to the 'I-I' mechanism, and we argue that within the 'I-I' regime (which displays a higher baseline oscillation frequency of ∼60 Hz), slight changes in the level of NMDA activity are inversely related to cycle frequency.