Social deficits and perseverative behaviors, but not overt aggression, in MAO-A hypomorphic mice

Neuropsychopharmacology. 2011 Dec;36(13):2674-88. doi: 10.1038/npp.2011.157. Epub 2011 Aug 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aggression*
  • Animals
  • Behavior, Animal / physiology*
  • Dendrites / enzymology
  • Dendrites / pathology
  • Disease Models, Animal
  • Frontal Lobe / abnormalities
  • Frontal Lobe / enzymology
  • Frontal Lobe / pathology
  • Humans
  • Male
  • Mental Disorders / enzymology*
  • Mental Disorders / genetics
  • Mental Disorders / physiopathology
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • Mice, Neurologic Mutants
  • Monoamine Oxidase / deficiency*
  • Monoamine Oxidase / genetics
  • Pyramidal Cells / enzymology
  • Pyramidal Cells / pathology
  • Social Behavior*
  • Stereotyped Behavior / physiology

Substances

  • Monoamine Oxidase