J Neurophysiol (April 1, 2003). 10.1152/jn.00943.2002
Submitted on Submitted 23 October 2002; accepted in final form 25 November 2002

Regulation of Neuronal Function by Choline and 4OH-GTS-21 Through 7 Nicotinic Receptors

Department of Pharmacology and Therapeutics, University of Florida College of Medicine, University of Florida, Gainesville, Florida 32610-0267

Uteshev, Vladimir V., Edwin M. Meyer, and Roger L. Papke. Regulation of Neuronal Function by Choline and 4OH-GTS-21 Through 7 Nicotinic Receptors. J. Neurophysiol. 89: 1797-1806, 2003. A unique feature of 7 nicotinic acetylcholine receptor physiology is that, under normal physiological conditions, 7 receptors are constantly perfused with their natural selective agonist, choline. Studying neurons of hypothalamic tuberomammillary (TM) nucleus, we show that choline and the selective 7 receptor agonist 4OH-GTS-21 can regulate neuronal functions directly, via activation of the native 7 receptors, and indirectly, via desensitizing those receptors or transferring them into a state "primed" for desensitization. The direct action produces depolarization and thereby increases the TM neuron spontaneous firing (SF) rate. The regulation of the spontaneous firing rate is robust in a nonphysiological range of choline concentrations >200 µM. However, modest effects persist at concentrations of choline that are likely to be attained perineuronally under some conditions (20-100 µM). At high physiological concentration levels, the indirect choline action reduces or even eliminates the responsiveness of 7 receptors and their availability to other strong cholinergic inputs. Similarly to choline, 4OH-GTS-21 increases the TM neuron spontaneous firing rate via activation of 7 receptors, and this regulation is robust in the range of clinically relevant concentrations of 4OH-GTS-21. We conclude that factors that regulate choline accumulation in the brain and in experimental slices such as choline uptake, hydrolysis of ACh, membrane phosphatidylcholine catabolism, and solution perfusion rate influence 7 nAChR neuronal and synaptic functions, especially under pathological conditions such as stroke, seizures, Alzheimer's disease, and head trauma, when the choline concentration in the CSF is expected to rise.