• Himashi Anver, Peter D Ward, Andor Magony, and Martin Vreugdenhil.
• Neuronal Networks Group, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
• Neuropsychopharmacology. 2011 Jan 1; 36 (2): 519-28.

AbstractHallucinations, a hallmark of psychosis, can be induced by the psychotomimetic N-methyl-D-aspartic acid (NMDA) receptor antagonists, ketamine and phencyclidine (PCP), and are associated with hypersynchronization in the γ-frequency band, but it is unknown how reduced interneuron activation associated with NMDA receptor hypofunction can cause hypersynchronization or distorted perception. Low-frequency γ-oscillations (LFγ) and high-frequency γ-oscillations (HFγ) serve different aspects of perception. In this study, we test whether ketamine and PCP affect the interactions between HFγ and LFγ in the rat visual cortex in vitro. In slices of the rat visual cortex, kainate and carbachol induced LFγ (∼ 34 Hz at 32°C) in layer V and HFγ (∼ 54 Hz) in layer III of the same cortical column. In controls, HFγ and LFγ were independent, and pyramidal neurons recorded in layer III were entrained by HFγ, but not by LFγ. Sub-anesthetic concentrations of ketamine selectively decelerated HFγ by 22 Hz (EC(50)=2.7 μM), to match the frequency of LFγ in layer V. This caused phase coupling of the two γ-oscillations, increased spatial coherence in layer III, and entrained the firing of layer III pyramidal neurons by LFγ in layer V. PCP similarly decelerated HFγ by 22 Hz (EC(50)=0.16 μM), causing cross-layer phase coupling of γ-oscillations. Selective NMDA receptor antagonism, selective NR2B subunit-containing receptor antagonism, and reduced D-serine levels caused a similar selective deceleration of HFγ, whereas increasing NMDA receptor activation through exogenous NMDA, D-serine, or mGluR group 1 agonism selectively accelerated HFγ. The NMDA receptor hypofunction-induced phase coupling of the normally independent γ-generating networks is likely to cause abnormal cross-layer interactions, which may distort perceptions due to aberrant matching of top-down information with bottom-up information. If decelerated HFγ and subsequent cross-layer synchronization also underlie pathological psychosis, acceleration of HFγ could be the target for improved antipsychotic therapy.

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