Calcium-induced calcium release in noradrenergic neurons of the locus coeruleus

The locus coeruleus (LC) is a nucleus within the brainstem that consists of norepinephrine-releasing neurons. It is involved in broad processes including cognitive and emotional functions. Understanding the mechanisms that control the excitability of LC neurons is important because they innervate widespread brain regions. One of the key regulators is cytosolic calcium concentration ([Ca²⁺]_c), the increases in which can be amplified by calcium-induced calcium release (CICR) from intracellular calcium stores. Although the electrical activities of LC neurons are regulated by changes in [Ca²⁺]_c, the extent of CICR involvement in this regulation has remained unclear. Here we show that CICR hyperpolarizes acutely dissociated LC neurons of the rat and demonstrate the underlying pathway. When CICR was activated by extracellular application of 10 mM caffeine, LC neurons were hyperpolarized in the current-clamp mode of patch-clamp recording, and the majority of neurons showed an outward current in the voltage-clamp mode. This outward current was accompanied by increased membrane conductance, and its reversal potential was close to the K⁺ equilibrium potential, indicating that it is mediated by opening of K⁺ channels. The outward current was generated in the absence of extracellular calcium and was blocked when the calcium stores were inhibited by applying ryanodine. Pharmacological blockers indicated that it was mediated by Ca²⁺-activated K⁺ channels of the non-small conductance type. The application of caffeine increased [Ca²⁺]_c, as visualized by fluorescence microscopy. These findings show CICR suppresses LC neuronal activity, and indicate its dynamic role in modulating the LC-mediated noradrenergic tone in the brain.