Regional localization and developmental profile of acetylcholinesterase-evoked increases in [(3)H]-5-fluororwillardiine binding to AMPA receptors in rat brain.
In addition to its role in hydrolyzing the neurotransmitter acetylcholine, the synaptically enriched enzyme acetylcholinesterase (AChE) has been reported to play an important role in the development and remodelling of neural processes and synapses. We have shown previously that AChE causes an increase in binding of the specific AMPA receptor ligand (S)-[(3)H]-5-fluorowillardiine ([(3)H]-FW) to rat brain membranes. In this study we have used quantitative autoradiography to investigate the regional distribution and age-dependence of AChE-evoked increases in the binding of [(3)H]-FW in rat brain. Pretreatment of rat brain sections with AChE caused a marked enhancement of [(3)H]-FW binding to many, but not all, brain areas. The increased [(3)H]-FW binding was blocked by the specific AChE inhibitor BW 284c51. The maximal potentiation of [(3)H]-FW binding occurred at different developmental age-points in different regions with a profile consistent with the peak periods for synaptogenesis in any given region. In addition to its effects on brain sections, AChE also strongly potentiated [(3)H]-FW binding to detergent solubilized AMPA receptors suggesting a direct action on the receptors themselves rather than an indirect effect on the plasma membrane. These findings suggest that modulation of AMPA receptors could provide one molecular mechanism for the previously reported effects of AChE on synapse formation, synaptic plasticity and neurodegeneration.
Olivera
S
S
MRC Centre for Synaptic Plasticity, Anatomy Department, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
Rodriguez-Ithurralde
D
D
Henley
J M
JM
D000110:Acetylcholinesterase / Q000187:drug effects / Q000494:pharmacology*; D000375:Aging / Q000502:physiology; D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D012995:Solubility; D014316:Tritium
D002800:Cholinesterase Inhibitors; D011743:Pyrimidines; D018091:Receptors, AMPA; D014316:Tritium; C095178:5-fluorowillardiine; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide; D000110:Acetylcholinesterase; D000409:Alanine; D007608:Kainic Acid