Reduced nicotinic receptor function in sympathetic ganglia is responsible for the hypothermia in the acetylcholinesterase knockout mouse.
Cholinergic signalling in the sympathetic ganglia (SG) contributes to non-shivering thermogenesis by relaying the activation signal from the brain to SG neurons which activate many peripheral tissues to produce heat. Paradoxically, acetylcholinesterase (AChE) inhibitors, which should enhance cholinergic signalling, induce hypothermia. To understand the mechanism of how cholinergic signalling in the SG controls thermoregulation, we analysed infant AChE knockout mice, which are known to show hypothermia by postnatal day 15. Nicotinic receptor currents were reduced in acutely dissociated SG neurons of the AChE-deficient mice by over 40% compared with wild-type mice. When wild-type neurons were treated for 1 h with either oxotremorine-M, a muscarinic agonist, or nicotine, the amplitude of nicotinic receptor currents was also decreased by 40%. The hypothermia in AChE mutant mice was fully rescued by a peripheral injection of both ivermectin, which increases nicotinic receptor currents, and methyl-atropine, a muscarinic antagonist. Our results demonstrate that the hypothermia induced by the lack of AChE activity is primarily caused by a downregulation of nicotinic receptors via prolonged stimulation of muscarinic and nicotinic receptors in SG neurons. The stationary noise analysis of the nicotinic receptor current traces showed that the properties of single-channel activities were not different between the two genotypes, suggesting that the primary reason for downregulation of nicotinic receptors is due to a reduction of the receptors on the surface.
Sun
Minjeong
M
Center for Neural Science, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Lee
C Justin
CJ
Shin
Hee-Sup
HS
D000110:Acetylcholinesterase / Q000235:genetics / Q000502:physiology*; D052436:Adipose Tissue, White / Q000503:physiopathology; D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology; D002799:Cholinergic Fibers / Q000502:physiology; D003080:Cold Temperature; D005728:Ganglia, Sympathetic / Q000502:physiology*; D005786:Gene Expression Regulation; D007035:Hypothermia / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D000110:Acetylcholinesterase