Sub-anesthetic doses of ketamine increase single cell entrainment in the rat auditory cortex during auditory steady-state response.

Abstract

Understanding the effects of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine on brain function is of considerable interest due to the discovery of its fast-acting antidepressant properties. It is well known that gamma oscillations are increased when ketamine is administered to rodents and humans, and increases in the auditory steady-state response (ASSR) have also been observed. To elucidate the cellular substrate of the increase in network activity and synchrony observed by sub-anesthetic doses of ketamine, the aim was to investigate spike timing and regularity and determine how this is affected by the animal's motor state. Single unit activity and local field potentials from the auditory cortex of awake, freely moving rats were recorded with microelectrode arrays during an ASSR paradigm. Ketamine administration yielded a significant increase in ASSR power and phase locking, both significantly modulated by motor activity. Before drug administration, putative fast-spiking interneurons (FSIs) were significantly more entrained to the stimulus than putative pyramidal neurons (PYRs). The degree of entrainment significantly increased at lower doses of ketamine (3 and 10 mg/kg for FSIs, 10 mg/kg for PYRs). At the highest dose (30 mg/kg), a strong increase in tonic firing of PYRs was observed. These findings suggest an involvement of FSIs in the increased network synchrony and provide a possible cellular explanation for the well-documented effects of ketamine-induced increase in power and synchronicity during ASSR. The results support the importance to evaluate different motor states separately for more translational preclinical research.