Antidromic burst activity of locus coeruleus neurons during cortical spreading depression

Abstract

The electrical activity of locus coeruleus neurons was investigated during cortical spreading depression in urethane-anaesthetized rats. Cortical spreading depression was induced by a direct application of 1–3 M KCl solution to the surface of the cerebral cortex. The occurrence of cortical spreading depression was assessed by recording negative d.c. shifts and in some experiments by monitoring the extracellular potassium concentrations. The mean spontaneous firing rate of locus coeruleus neurons was significantly reduced during cortical spreading depression. Approximately 60% of locus coeruleus neurons recorded during cortical spreading depression revealed anomalous burst activity consisting of multiple initial segment spikes as well as full initial segment-somatodendritic spikes with a marked initial segment-somatodendritic break. Each spike of the cortical spreading depression-related burst activity occurred at intervals ranging from 15.0 ms to 90.1 ms (34.9±0.5 ms). The burst activity appeared unpredictably at variable intervals in a phasic or tonic manner during cortical spreading depression. The cortical spreading depression-related burst activity of locus coeruleus neurons mimicked antidromic spikes induced by train stimulation of the cerebral cortex at short interspike intervals during iontophoretic application of GABA to locus coeruleus neurons, whereas it was totally different from synaptically-activated burst activity induced by tail pinch. The full spikes and initial segment spikes in the cortical spreading depression-related burst activity failed to collide with cortically elicited antidromic spikes, even when they appeared within the collision interval. The proportion of initial segment spikes in the cortical spreading depression-related burst activity was reduced following an increase in membrane excitability by iontophoretic application of glutamate, and increased during a decreased membrane excitability by GABA application. The antidromic burst activity of locus coeruleus neurons also appeared for a short time during cortical spreading depression prior to the occurrence of seizure waves induced by GABA antagonists, while the burst activity could not be observed during seizure activity. These results indicate that the cortical spreading depression-related burst activity was of antidromic origin and that the marked initial segment-somatodendritic break in spontaneous spikes of locus coeruleus neurons during cortical spreading depression was due to reduced excitability of the somatodendritic membrane. The cortical spreading depression-related burst activity may cause release of a large amount of noradrenaline in vast regions of locus coeruleus terminal fields through the numerous axon collaterals, thereby playing a role in functional changes of brain neurons related to cortical spreading depression.