NMDA receptor hypofunction phase-couples independent gamma oscillations in the rat visual cortex.

Himashi Anver (1) , Peter D Ward (1) , Andor Magony (1) , Martin Vreugdenhil (1)

1 Neuronal Networks group, school of Clinical and Experimental Medicine

Hallucinations, a hallmark of psychosis, can be induced by the psychotomimetic NMDA receptor antagonists ketamine and phencyclidine and are associated with hypersynchronization in the gamma frequency band, but it is unknown how reduced interneuron activation, associated with NMDA receptor hypofunction can cause hypersynchronisation or distorted perception. Low-frequency gamma oscillations (LFγ) and high-frequency gamma oscillations (HFγ) serve different aspects of perception. Here we test whether ketamine and phencyclidine are able to 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 ºC) in layer V and HFγ (~54 Hz) in layer III of the same cortical column. In control HFγ and LFγ were independent and pyramidal neurons recorded in layer III were entrained by HFγ, but not by LFγ. Sub-anaesthetic concentrations of ketamine selectively decelerated HFγ by 22 Hz (EC50= 2.7 µM), to match the frequency of LFγ in layer V. This caused phase-coupling of the two gamma oscillations, increased spatial coherence in layer III and entrained the firing of layer III pyramidal neurons by LFγ in layer V. Phencyclidine similarly decelerated HFγ by 22 Hz (EC50= 0.16 µM), causing cross-layer phase-coupling of gamma 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 gamma-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 synchronisation also underlies pathological psychosis, acceleration of HFγ could be the target for improved antipsychotic therapy.

Mots clés: Schizophrenia; Antipsychotics; Psychopharmacology; Cognition; Addiction & Substance Abuse; Gamma oscillation; ketamine; phencyclidine; hallucinogenic; psychotomimetic

Himashi Anver, Peter D Ward, Andor Magony, Martin Vreugdenhil. NMDA receptor hypofunction phase-couples independent gamma oscillations in the rat visual cortex.. Neuropsychopharmacology, 2010, ⟨10.1038/npp.2010.183⟩. ⟨hal-00587265⟩