Effects of BDNF infusion on the regulation of TrkB protein and message in adult rat brain.
Exposure of embryonic CNS neurons to BDNF in vitro causes down-regulation of TrkB protein and mRNA, and an attenuation of functional responses to acute neurotrophin stimulation. In order to investigate ligand-mediated regulation of TrkB in vivo, we infused BDNF into the midbrain, near the periaquaductal grey-dorsal raphe (PAG-DR), or into the olfactory bulb of adult rats. Midbrain infusion of BDNF produced analgesia that was sustained for the duration of BDNF delivery. Analysis of TrkB receptor levels revealed that at the point when the maximal analgesic effect of BDNF was obtained, there was a concommitant 75% decrease in full-length TrkB protein at the infusion site. After discontinuation of infusion, levels of TrkB recovered toward base line. Interestingly, TrkB protein levels were not accompanied by decreased trkB mRNA levels. To determine if BDNF infusion decreased TrkB protein levels in other brain areas and whether trkB mRNA might be down-regulated in the cell bodies of neurons projecting to the infusion site, we infused BDNF into the olfactory bulb. Following a 12-day infusion of BDNF, TrkB protein levels decreased within the bulb to a similar extent as in the PAG-DR. This decrease in receptor protein, however, was not accompanied by decreased trkB mRNA levels in the olfactory cortex, which is afferent to the bulb. Taken together, our data suggest that decreases in TrkB receptor protein at the site of BDNF infusions in the adult brain represent receptor turnover, but this is not associated with altered expression of trkB mRNA or attenuation of the pharmacological effects of BDNF.
Frank
L
L
Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA.
Wiegand
S J
SJ
Siuciak
J A
JA
Lindsay
R M
RM
Rudge
J S
JS
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001692:Biological Transport / Q000502:physiology; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D008297:Male; D008636:Mesencephalon / Q000737:chemistry / Q000166:cytology; D009474:Neurons / Q000737:chemistry / Q000166:cytology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D009830:Olfactory Bulb / Q000737:chemistry / Q000166:cytology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics* / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor