Cholinergic Stress Signals Accompany MicroRNA-Associated Stereotypic Behavior and Glutamatergic Neuromodulation in the Prefrontal Cortex

Stereotypic behavior (SB) is common in emotional stress-involved psychiatric disorders and is often attributed to glutamatergic impairments, but the underlying molecular mechanisms are unknown. Given the neuro-modulatory role of acetylcholine, we sought behavioral-transcriptomic links in SB using TgR transgenic mice with impaired cholinergic transmission due to over-expression of the stress-inducible soluble ‘readthrough’ acetylcholinesterase-R splice variant AChE-R. TgR mice showed impaired organization of behavior, performance errors in a serial maze test, escape-like locomotion, intensified reaction to pilocarpine and reduced rearing in unfamiliar situations. Small-RNA sequencing revealed 36 differentially expressed (DE) microRNAs in TgR mice hippocampi, 8 of which target more than 5 cholinergic transcripts. Moreover, compared to FVB/N mice, TgR prefrontal cortices displayed individually variable changes in over 400 DE mRNA transcripts, primarily acetylcholine and glutamate-related. Furthermore, TgR brains presented c-fos over-expression in motor behavior-regulating brain regions and immune-labeled AChE-R excess in the basal ganglia, limbic brain nuclei and the brain stem, indicating a link with the observed behavioral phenotypes. Our findings demonstrate association of stress-induced SB to previously unknown microRNA-mediated perturbations of cholinergic/glutamatergic networks and underscore new therapeutic strategies for correcting stereotypic behaviors.

Authors: Moshitzky, G.; Shoham, S.; Madrer, N.; Husain, A.M.; Greenberg, D.S.; Yirmiya, R.; Ben-Shaul, Y.; Soreq, H.
Year of publication: 2020
Journal: Biomolecules 10, 848

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