title: AMPA receptor potentiation by acetylcholinesterase is age-dependently upregulated at synaptogenesis sites of the rat brain.
abstract: We have used radioligand binding to synaptic membranes from distinct rat brain regions and quantitative autoradiography to investigate the postnatal evolution of acetylcholinesterase (AChE)-evoked up-regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in CNS areas undergoing synaptogenesis. Incubation of synaptosomal membranes or brain sections with purified AChE caused a developmentally modulated enhancement in the binding of [3H]-(S)-AMPA and the specific AMPA receptor ligand [3H]-(S)-5-fluorowillardiine, but did not modify binding to kainate neither N-methyl-D-aspartate receptors. In all postnatal ages investigated (4, 7, 14, 20, 27, 40 days-old and adult rats), AChE effect on binding was concentration-dependent and blocked by propidium, BW 284c51, diisopropylfluorophosphonate and eserine, therefore requiring indemnity of both peripheral and active sites of the enzyme. AChE-mediated enhancement of [3H]-fluorowillardiine binding was measurable in all major CNS areas, but displayed remarkable anatomical selectivity and developmental regulation. Autoradiograph densitometry exhibited distinct temporal profiles and peaks of treated/control binding ratios for different cortices, cortical layers, and nuclei. Within the parietal, occipital and temporal neocortices, hippocampal CA1 field and cerebellum, AChE-potentiated binding ratios peaked in chronological correspondence with synaptogenesis periods of the respective AMPA-receptor containing targets. This modulation of AMPA receptors by AChE is a molecular mechanism able to transduce localized neural activity into durable modifications of synaptic molecular structure and function. It might also contribute to AChE-mediated neurotoxicity, as postulated in Alzheimer's disease and other CNS disorders.
authors.affiliation: Molecular Neuroscience Unit, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia 3318, 11600, Montevideo, Uruguay.
authors.forename: Silvia
authors.initials: S
authors.lastname: Olivera
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henley
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodriguez-Ithurralde
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism* / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000409:Alanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013569:Synapses / Q000502:physiology; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D011743:Pyrimidines; D018091:Receptors, AMPA; C095178:5-fluorowillardiine; D000110:Acetylcholinesterase; D000409:Alanine