title: Social deficits and perseverative behaviors, but not overt aggression, in MAO-A hypomorphic mice.
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-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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.forename: Sean C
authors.initials: SC
authors.lastname: Godar
authors.forename: Gao
authors.initials: G
authors.lastname: Chen
authors.forename: Weihua
authors.initials: W
authors.lastname: Wu
authors.forename: Igor
authors.initials: I
authors.lastname: Rebrin
authors.forename: Mollee R
authors.initials: MR
authors.lastname: Farrell
authors.forename: Anna L
authors.initials: AL
authors.lastname: Scott
authors.forename: Cara L
authors.initials: CL
authors.lastname: Wellman
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
mesh_terms: D000374:Aggression; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003712:Dendrites / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000002:abnormalities / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D017966:Pyramidal Cells / Q000201:enzymology / Q000473:pathology; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000502:physiology
chemical_list: D008995:Monoamine Oxidase