Journal
NEUROPSYCHOPHARMACOLOGY
Volume 36, Issue 13, Pages 2674-2688Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2011.157
Keywords
monoamine oxidase-A; transgenic mice; social interaction; aggression; anxiety; repetitive behaviors
Categories
Funding
- National Institutes of Health [R01MH39085, R37MH39085, R21HD070611, R03MH087794]
- Boyd and Elsie Welin Professorship
- US-Israel Binational Science Foundation [2007096]
- Zumberge USC Research Grant
- Tourette Syndrome Association
- Newron Pharmaceuticals
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
- National Institute of Mental Health
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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-A(Neo) 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-A(Neo) mice. In the prefrontal cortex and amygdala, MAO-A(Neo) 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-A(Neo) mice featured a neurochemical profile akin to MAO-A-knockout (KO) mice, with undetectable MAO-A activity and high 5-HT concentrations. MAO-A(Neo) 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-A(Neo) 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-A(Neo) 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. Neuropsychopharmacology (2011) 36, 2674-2688; doi: 10.1038/npp.2011.157; published online 10 August 2011
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