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.
Dong
Haiheng
H
Sunnybrook and Women's College Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada M4N 3M5.
Xiang
Yun-Yan
YY
Farchi
Noa
N
Ju
William
W
Wu
Yaojiong
Y
Chen
Liwen
L
Wang
Yutian
Y
Hochner
Binyamin
B
Yang
Burton
B
Soreq
Hermona
H
Lu
Wei-Yang
WY
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