Previously we have demonstrated that gamma band (20-80 Hz) oscillations can be elicited in the medial entorhinal cortex (mEC) by the application of nanomolar concentration of kainate (Cunningham et al. 2002). The mEC is an association centre located in a strategic position in the cortical-hippocampal axis of the medial temporal lobe. It is known that abnormalities in the mEC have been implicated in the pathology of schizophrenia (Harrison, 1999). Ketamine is a dissociative anaesthetic agent, known to induce severe psychosis in humans. The aim of this work was to investigate the action of ketamine on gamma oscillations in the mEC.

Combined entorhinal-hippocampal slices (~450 mm) were taken from adult (200-250 g) Wistar rats after terminal anaesthesia using ketamine-xylazine (administered intramuscularly), and intracardial perfusion with artificial cerebrospinal fluid (ACSF) in which NaCl was replaced with sucrose. Slices were maintained at an interface of oxygenated ACSF and humidified (95 % O₂ and 5 % CO₂) gas at 36 °C. Extracellular field recordings were made in the superficial and deep layers of the mEC, using glass microelectrodes containing ACSF (resistance < 3 MΩ). Student’s t test was used to compare the data.

Gamma activity was evoked by bath perfusion of the AMPA/kainate receptor agonist kainic acid (400 nM) alone. Ketamine was bath applied at concentrations of 10, 20 and 50 mM. At concentrations of 20 mM ketamine, superficial gamma peak power and area was significantly reduced (P < 0.05; n = 8), although in the deep layers no such effect was observed. In both layers, the peak frequency of the gamma activity was reduced significantly at 20 mM ketamine (P < 0.05). In terms of rhythmicity, the superficial layers were also selectively more sensitive than deep layers. Auto-correlation analysis of activity in both layers revealed significant (P < 0.05) reductions in this behaviour at 10 mM in the superficial layers, whereas a significant effect was not seen until a concentration of 20 mM in the deep layer. Ketamine is known to act at NMDA receptors. Indeed, gamma activity in the mEC was shown to be inhibited by the application of the non-competitive NMDA antagonist D-APV. However, the pre-application of D-APV was unsuccessful in occluding the action of ketamine on residual gamma activity in the mEC.

These results demonstrate that gamma activity in the mEC is disrupted by ketamine. Superficial gamma activity was particularly sensitive and since the superficial layers are the main output of the mEC to the hippocampus and higher cortical areas, this may have important implications in the study of psychosis. In addition, these data suggest that the effects of ketamine on gamma activity involve mechanisms in addition to non-competitive NMDA blockade.

This work was supported by the MRC.

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