Synaptogenesis and myopathy under acetylcholinesterase overexpression

Environmental congenital, and acquired immunological insults perturbing neu romuscular junction (NMJ) activity may induce a variety of debilitating neu romuscular pathologies. However, the molecular elements linking NMJ dysfunc tion to long-term myopathies are unknown. Here, we report dramatically elev ated levels of mRNA encoding c-Fos and the "readthrough" (R) variant of ace tylcholinesterase (AChE) in muscles of transgenic mice overexpressing synap tic (S) AChE in motonenrons and in control mice treated with the irreversib le cholinesterase inhibitor diisopropylfluorophosphonate (DFP). Tongue musc les from DFP-treated and AChE-S transgenic mice displayed exaggerated neuri te branching and disorganized, wasting fibers. Moreover, diaphragm muscles from both transgenic and DFP-treated mice exhibited NMJ proliferation. 2'-O -methyl-protected antisense oligonucleotides targeted to AChE mRNA suppress ed feedback upregulation of AChE and ameliorated DFP-induced NMJ proliferat ion. Our findings demonstrate common transcriptional responses to cholinerg ic NMJ stress of diverse origin, and implicate deregulated AChE expression in excessive neurite outgrowth, uncontrolled synaptogenesis, and myopatholo gy.