期刊
BIOLOGICAL PSYCHIATRY
卷 60, 期 7, 页码 741-751出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2006.03.080
关键词
AChE; antisense; catalepsy; neuroleptics; stress; tetracycline-controlled transgenics
Background: Cholinergic neurotransmission notably participates in stress-induced motor responses. Here we report the contribution of alternative splicing of acetylcholinesterase (ACNE) pre-mRNA to modulate these responses. More specifically, we induced stress-associated hypofunction of dopaminergic, mainly D2 dopamine receptor-mediated neurotransmission by haloperidol and explored stress induced hyperlocomotion and catalepsy, an extreme form of immobility, induced in mice with ACNE deficiencies. Methods: Conditional transgenic (Tet/AS) spice were created with tetracycline-induced antisense suppression of ACNE gene expression. Locomotion and catalepsy times were measured in Tet/AS and strain-matched control mice, under open field exposure threat and under home-cage safety. Results: In vitro, NGF-treated PC12 cells failed to extend neurites upon Tet/AS suppression. In vivo, Tet/AS but not control mice showed stress-associated hippocampal deposits of heat-shock protein 70 and GRP78 (BiP), predicting posttranscriptional changes in neuronal reactions. Supporting this notion, their striatal cholinergic neurons demonstrated facilitated capacity for neurite extension, attributing these in vivo changes in neurite extension to network interactions. Tet/AS mice presented stress-induced hyperlocomotion. Moreover, the dopamine antagonist haloperidol induced longer catalepsy in threatened Tet/AS than in control mice. When returned to home-cage safety, Tet/AS mice showed retarded release from catalepsy. Conclusions: Acetylcholinesterase modulates stress-induced motor responses and facilitates resumption of normal motor behavior following stress through both catalytic and noncatalytic features.
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