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The Journal of Neuroscience, October 13, 2004, 24(41):8950-8960; doi:10.1523/JNEUROSCI.2106-04.2004

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Cellular/Molecular
Excessive Expression of Acetylcholinesterase Impairs Glutamatergic Synaptogenesis in Hippocampal Neurons

Haiheng Dong,^1,2 Yun-Yan Xiang,^1,2 Noa Farchi,^4,5 William Ju,³ Yaojiong Wu,^1,3 Liwen Chen,^1,3 Yutian Wang,³ Binyamin Hochner,⁴ Burton Yang,^1,3 Hermona Soreq,⁵ and Wei-Yang Lu^1,2

¹Sunnybrook and Women's College Health Sciences Centre, Departments of ²Anesthesia, ³Laboratory Medicine, and Pathobiology, University of Toronto, Toronto, Ontario, Canada M4N 3M5, Departments of ⁴Neurobiology and ⁵Biological Chemistry, Institute of Life Sciences, and The Israel Center for Neuronal Computation, The Hebrew University of Jerusalem, Israel 91905

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 -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 -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.

Key words: anticholinesterase; cytoarchitecture; growth cone; neurexin; neuroligin; peripheral anion site

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Received May 31, 2004; revised July 20, 2004; accepted August 12, 2004.

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