Demonstration of functional alpha4-containing nicotinic receptors in the medial habenula.
The medial habenula (MHb) exhibits exceptionally high levels of nicotinic acetylcholine receptors (nAChRs), but it remains unclear whether all expressed nAChR subunit mRNAs are translated to form functional receptors. In particular alpha4 subunits have not been reported to have any functional role, despite strong alpha4 mRNA expression in the ventrolateral MHb. We studied a strain of knock-in mice expressing fluorescent alpha4* nAChRs (alpha4YFP), as well as a knock-in strain expressing hypersensitive alpha4* nAChRs (alpha4L9'A). In alpha4YFP mice, there was strong fluorescence in the ventrolateral MHb. In hypersensitive alpha4L9'A mice, injections of a low dose of nicotine (0.1 mg/kg) led to strong c-fos expression in only the ventrolateral region of the MHb, but not in the MHb of wild-type (WT) mice. In MHb slice recordings, ventrolateral neurons from alpha4L9'A mice, but not from WT mice, responded robustly to nicotine (1 microM). Neurons in the medial aspect of the MHb had >10-fold smaller responses. Thus alpha4* nAChRs contribute to the selective activation of a subset of MHb neurons. Subunit composition analysis based on gain-of-function knock-in mice provides a useful experimental paradigm.
Fonck
Carlos
C
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
Nashmi
Raad
R
Salas
Ramiro
R
Zhou
Chunyi
C
Huang
Qi
Q
De Biasi
Mariella
M
Lester
Robin A J
RA
Lester
Henry A
HA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019262:Habenula / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008164:Luminescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009538:Nicotine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*
D008164:Luminescent Proteins; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D009538:Nicotine
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