Excessive expression of acetylcholinesterase impairs glutamatergic synaptogenesis in hippocampal neurons.
Acetylcholinesterase (AChE) exerts noncatalytic activities on neural cell differentiation, adhesion, and neuritogenesis independently of its catalytic function. The noncatalytic functions of AChE have been attributed to its peripheral anionic site (PAS)-mediated protein-protein interactions. Structurally, AChE is highly homologous to the extracellular domain of neuroligin, a postsynaptic transmembrane molecule that interacts with presynaptic beta-neurexins, thus facilitating synaptic formation and maturation. Potential effects of AChE expression on synaptic transmission, however, remain unknown. Using electrophysiology, immunocytochemistry, and molecular biological approaches, this study investigated the role of AChE in the regulation of synaptic formation and functions. We found that AChE was highly expressed in cultured embryonic hippocampal neurons at early culture days, particularly in dendritic compartments including the growth cone. Subsequently, the expression level of AChE declined, whereas synaptic activity and synaptic proteins progressively increased. Chronic blockade of the PAS of AChE with specific inhibitors selectively impaired glutamatergic functions and excitatory synaptic structures independently of cholinergic activation, while inducing AChE overexpression. Moreover, the PAS blockade-induced glutamatergic impairments were associated with a depressed expression of beta-neurexins and an accumulation of other synaptic proteins, including neuroligins, and were mostly preventable by antisense suppression of AChE expression. Our findings demonstrate that interference with the nonenzymatic features of AChE alters AChE expression, which impairs excitatory synaptic structure and functions.
Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5.
Haiheng
H
Dong
Yun-Yan
YY
Xiang
Noa
N
Farchi
William
W
Ju
Yaojiong
Y
Wu
Liwen
L
Chen
Yutian
Y
Wang
Binyamin
B
Hochner
Burton
B
Yang
Hermona
H
Soreq
Wei-Yang
WY
Lu
D000110:Acetylcholinesterase / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D020439:Growth Cones / Q000201:enzymology / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D017403:In Situ Hybridization; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; C086959:neurexin Ibeta; D018698:Glutamic Acid; D000110:Acetylcholinesterase