Ketamine Disrupts Theta Modulation of Gamma in a Computer Model of Hippocampus

Abstract

Abnormalities in oscillations have been suggested to play a role in schizophrenia. We studied theta-modulated gamma oscillations in a computer model of hippocampal CA3 in vivo with and without simulated application of ketamine, an NMDA receptor antagonist and psychotomimetic. Networks of 1200 multi-compartment neurons (pyramidal, basket and oriens-lacunosum moleculare, OLM, cells) generated theta and gamma oscillations from intrinsic network dynamics: basket cells primarily generated gamma and amplified theta, while OLM cells strongly contributed to theta. Extrinsic medial septal inputs paced theta and amplified both theta and gamma oscillations. Exploration of NMDA receptor reduction across all location combinations demonstrated that the experimentally-observed ketamine effect occurred only with isolated reduction of NMDA receptors on OLMs. In the ketamine simulations, lower OLM activity reduced theta power and disinhibited pyramidal cells, resulting in increased basket cell activation and gamma power. Our simulations predict: ketamine increases firing rates;oscillations can be generated by intrinsic hippocampal circuits;medial septum inputs pace and augment oscillations;pyramidal cells lead basket cells at the gamma peak but lag at trough;basket cells amplify theta rhythms;ketamine alters oscillations due to primary blockade at OLM NMDA receptors;ketamine alters phase relationships of cell firing;ketamine reduces network responsivity to the environmentketamine effect could be reversed by providing a continuous inward current to OLM cells. We suggest that this last prediction has implications for a possible novel treatment for cognitive deficits of schizophrenia by targeting OLM cells.

Theta-associated high-frequency oscillations (110–160Hz) in the hippocampus and neocortex

“…13). For instance, PAC could stem from pulses of inhibition paced at the slower frequency and targeted at the generators of the faster oscillation Neymotin et al, 2011;Tort et al, 2007;Wulff et al, 2009). One concept on the mechanisms underlying HFOs postulates that rhythmic activity is generated within a plexus of electrically coupled axons (Traub , 2002, 2003).…”

Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice

“…The latency (a) and the duration (b) of loss of righting reflex were recorded. All values are expressed as the mean ± SEM are mainly attributed to the NMDAR blockade, as it is a prominent feature of most NMDAR antagonist compounds (Nakao et al 2003;Neymotin et al 2011;Thomson et al 1985;Vollenweider and Geyer 2001). Betaine might counteract the psychotomimetic effects of ketamine through modulating the NMDAR glycine binding site since the beneficial effect of betaine in the NORT was significantly attenuated by 7-chlorokynurenic acid (7-CTKA), an antagonist for the NMDAR glycine binding site (Supplement 1).…”

“…Several drugs that effectively either block or antagonize NMDAR activity, such as the competitive NMDAR antagonists CGP 37849 and CGP 40116 (Papp and Moryl 1994), the noncompetitive, nonsubunit selective NMDAR antagonist MK-801 (Autry et al 2011;Lima-Ojeda et al 2013;Maeng et al 2008), and the NR2B selective antagonist RO-25-6981 (Lima-Ojeda et al 2013;Maeng et al 2008), have repeatedly and consistently been shown to have antidepressant-like properties in rodent models. NMDAR blockade is also the main contributor of the psychotomimetic effects of ketamine, as most NMDAR antagonist compounds have the same properties (Nakao et al 2003;Neymotin et al 2011;Thomson et al 1985;Vollenweider and Geyer 2001). On the other hand, enhancement of NMDAR function, via activation of glycine binding site or modulation of metabotropic glutamate receptors, represents a promising approach to reverse psychotomimetic effects of ketamine (Chan et al 2008;Krystal et al 2005;Roberts et al 2010;Yang et al 2010) or other NMDAR antagonists (Kanahara et al 2008;Kawaura et al 2015;Lipina et al 2005;Santini et al 2014).…”

Disturbed theta and gamma coupling as a potential mechanism for visuospatial working memory dysfunction in people with schizophrenia

“…Neymotin and colleagues [64] used a computer model of hippocampal CA3 to investigate the effect of the application of simulated ketamine. Ketamine administration disrupted theta-gamma coupling in the simulation, apparently due to its antagonistic effect on NMDA receptors on orienslacunosum moleculare cells (OLM); normal coupling was restored via injection of a continuous, depolarizing current into these OLM cells, suggesting a potential intervention for treating deficits in WM and other cognitive processes in PSZ.…”