Somatic Ca(2+) dynamics in response to choline-mediated excitation in histaminergic tuberomammillary neurons

Histaminergic tuberomammillary (TM) neurons of the posterior hypothalamus have been implicated in cognition, alertness and sleep-wakefulness cycles. Spontaneous firing of TM neurons has been associated with histamine release and wakefulness. The expression of alpha7 nicotinic acetylcholine receptors (nAChRs) in TM neurons suggests a role for endogenous choline and for nicotinic drugs in the regulation of intracellular Ca(2+) metabolism, normal TM neuronal activity and histamine release. First, we established the link between TM neuronal spontaneous firing frequency and cytosolic free Ca(2+) concentration ([Ca(2+)](i)). A strong correlation was observed: an onset of spontaneous firing (3-4Hz) was accompanied by a 20-fold increase in [Ca(2+)](i) from 56+/-18 nM to 1.0+/-0.6 microM. The same range of firing frequencies has been observed in TM neurons in vivo and is associated with wakefulness. Secondly, choline-induced activation of alpha7 nAChRs did not elevate [Ca(2+)](i) directly, i.e. in the absence of high-threshold voltage-gated Ca(2+) channel (HVGCC) activation. Cd(2+) (200 microM) completely blocked all Ca(2+) signals, but inhibited only 37+/-16% of alpha7 nAChR-mediated currents. Thirdly, the responsiveness of [Ca(2+)](i) to choline-mediated excitation was inhibited by hyperpolarization and enhanced by depolarization, sensitizing [Ca(2+)](i) at membrane voltages associated with normal TM neuronal activity. These properties of [Ca(2+)](i) define the ability of TM neurons to translate cholinergic stimuli of identical strengths into different cytosolic Ca(2+) effects, providing the physiological substrate for state-specific modulation of incoming cholinergic information and would be expected to play a very important role in determining activity profiles of TM neurons exposed to elevated concentrations of cholinergic agents, such as choline and nicotine.