Modulation of locus coeruleus neurons and strong release of noradrenaline during acute hippocampal seizures in rats

The locus coeruleus (LC), a brainstem nucleus, is the sole source of noradrenaline in the neocortex, hippocampus and cerebellum. Noradrenaline is a powerful neuromodulator involved in the regulation of excitability and plasticity of large-scale brain networks. In this study, we assessed the activity of locus coeruleus neurons and changes in noradrenergic transmission during acute hippocampal seizures evoked with perforant path stimulation. LC neurons were recorded in anesthetized rats using a multichannel electrophysiology probe and were identified based on electrophysiological characteristics or optogenetic tagging. The majority of LC neurons (55%) were inhibited during seizures, while only a subset of LC neurons (28%) was excited during seizures. Topographic analysis of multi-unit activity showed anatomical separation of neurons that were excited and inhibited during seizures. Changes in hippocampal noradrenaline transmission during seizures were assessed using a fluorescent biosensor for noradrenaline, GRABNE2m, in combination with fiber photometry in both anesthetized and awake rats. Our results indicate that acute electrically evoked hippocampal seizures are associated with strong changes in LC unit activity and strong and consistent time-locked release of noradrenaline. Understanding the role of mass release of noradrenaline during hippocampal seizures is likely to be important to understand seizure pathophysiology.