Abstract
Monoamine oxidase (MAO)-A is a key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE). In humans and mice, total MAO-A deficiency results in high 5-HT and NE levels, as well as elevated reactive aggression. Here we report the generation of MAO-ANeo mice, a novel line of hypomorphic MAO-A mutants featuring the insertion of a floxed neomycin-resistance cassette in intron-12 of the Maoa gene. This construct resulted in a chimeric, non-functional variant of the Maoa-Neo transcript, with a truncated C-terminus, likely due to aberrant splicing; these deficits notwithstanding, small amounts of functional Maoa transcript were found in the brain of MAO-ANeo mice. In the prefrontal cortex and amygdala, MAO-ANeo mice showed low, yet detectable, MAO-A catalytic activity, as well as 5-HT levels equivalent to WT littermates; conversely, the hippocampus and midbrain of MAO-ANeo mice featured a neurochemical profile akin to MAO-A-knockout (KO) mice, with undetectable MAO-A activity and high 5-HT concentrations. MAO-ANeo mice showed significant increases in dendritic length in the pyramidal neurons of orbitofrontal cortex, but not basolateral amygdala, in comparison with WT littermates; by contrast, the orbitofrontal cortex of MAO-A KO mice showed significant reductions in basilar dendritic length, as well as a profound increase in apical dendritic length. MAO-ANeo mice showed a unique set of behavioral abnormalities, encompassing reduced open-field locomotion, perseverative responses, such as marble burying and water mist-induced grooming, and a lack of anxiety-like behaviors in the elevated plus-maze and light–dark box paradigms. Notably, whereas MAO-ANeo and KO mice showed significant reductions in social interaction, only the latter genotype showed increases in resident–intruder aggression. Taken together, our findings indicate that MAO A hypomorphism results in behavioral and morphological alterations distinct from those featured by MAO-A KO mice.
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Acknowledgements
The present study was supported by National Institutes of Health grants R01MH39085 (to JCS), R37MH39085 (MERIT Award) (to JCS), R21HD070611 (to MB), R03MH087794 (to CLW), as well as the Boyd and Elsie Welin Professorship (to JCS), US–Israel Binational Science Foundation Grant 2007096 (to CLW) and the Zumberge USC Research Grant (to MB). We thank TJ Ley for providing the pPGKneo-I vector. We are grateful to the USC transgenic core facility, Eric Ka-Wai Hui, Bin Qian, Jia Lu, Lauren Burgeno, Paradai Adysayathephkul, Mona Dousti, and Felix Li for technical assistance.
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Dr M Bortolato reports that, over the past 2 years, he has received research funding support from the Tourette Syndrome Association, Newron Pharmaceuticals, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Drs K Chen, SC Godar, G Chen, W Wu, I Rebrin, MR Farrel, and AL Scott have nothing to disclose. Dr CL Wellman has received funding support from the US–Israel Binational Science Foundation and the National Institute of Mental Health. Dr JC Shih has received funding support from the National Institute of Mental Health.
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Bortolato, M., Chen, K., Godar, S. et al. Social Deficits and Perseverative Behaviors, but not Overt Aggression, in MAO-A Hypomorphic Mice. Neuropsychopharmacol 36, 2674–2688 (2011). https://doi.org/10.1038/npp.2011.157
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