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

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Pharmacological rescue of mutated Kv3.1 ion-channel linked to progressive myoclonus epilepsies.

Progressive myoclonus epilepsies (PMEs) constitute a cluster of inherent, genetically diverse, rare seizure disorders characterized by ataxia, tonic-clonic seizures, and action myoclonus. Recently, a mutation in the KCNC1 gene (Arg320His) was described in a group of PME patients. The KCNC1 gene encodes the Kv3.1 potassium ion channel responsible for the rapid repolarization of the membrane potential following action potential firing in fast spiking GABAergic interneurons (FSI), thereby enabling high firing frequency. In the present study, we demonstrate that the Arg320His mutation cause a reduction in the Kv3.1 current amplitude and acts in a dominantly negative fashion. The mutation profoundly affects channel activation and deactivation kinetics, and we further find that it impairs recruitment of the Kv3.1 channel to the plasma membrane. The Kv3 activating compound, RE01, partly rescues the electrophysiological deficit, suggesting that pharmacological activation of Kv3.1 activity might be a feasible approach for treatment of this cohort of PME patients.

Visual patch clamp recording of neurons in thick portions of the adult spinal cord.

The study of visually identified neurons in slice preparations from the central nervous system offers considerable advantages over in vivo preparations including high mechanical stability in the absence of anaesthesia and full control of the extracellular medium. However, because of their relative thinness, slices are not appropriate for investigating how individual neurons integrate synaptic inputs generated by large numbers of neurons. Here we took advantage of the exceptional resistance of the turtle to anoxia to make slices of increasing thicknesses (from 300 to 3000 microm) from the lumbar enlargement of the spinal cord. With a conventional upright microscope in which the light condenser was carefully adjusted, we could visualize neurons present at the surface of the slice and record them with the whole-cell patch clamp technique. We show that neurons present in the middle of the preparation remain alive and capable of generating action potentials. By stimulating the lateral funiculus we can evoke intense synaptic activity associated with large increases in conductance of the recorded neurons. The conductance increases substantially more in neurons recorded in thick slices suggesting that the size of the network recruited with the stimulation increases with the thickness of the slices. We also find that that the number of spontaneous excitatory postsynaptic currents (EPSCs) is higher in thick slices compared with thin slices while the number of spontaneous inhibitory postsynaptic currents (IPSCs) remains constant. These preliminary data suggest that inhibitory and excitatory synaptic connections are balanced locally while excitation dominates long-range connections in the spinal cord.