A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior

Abstract

A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased, and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/ escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis of disorders associated with abnormal monoamine neurotransmitters. (21), indicating that the increase in 5-HT, a preferred substrate for MAO A, and concomitant decrease in 5-HIAA may form the basis for increased aggression, consistent with the association of low 5-HIAA levels in the cerebrospinal fluid of men who exhibit aggressive behavior (22,23). Although increased aggressive behavior has not been observed in MAO B KO mice (21), low platelet MAO B activity in humans is associated with, and considered a marker for, criminal or impulsive behavior (24), although whether this is accompanied in human subjects by a concomitant decrease in MAO A activity or other related genetic or biochemical aberration is not known.MAO A/B KO mice cannot be generated through the breeding of MAO A KO and MAO B KO mice, due to the close proximity of the isoenzyme genes on the X chromosomes, where the two genes are next to each other at their 3Ј tails, organized in opposite orientations with their last exons being less than 24 kb apart (determined by blat analysis of human and mouse MAO A and B

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

“…In addition, we found an increased adult hippocampal neurogenesis in MAO A/B KO mice. The present results complement and extend previous findings from our group and others on the characterization of the phenotypic consequences of combined MAO A and MAO B deficiency in humans and mice (12,(14)(15)(16)18). MAO A/B KO mice exhibited a statistical trend (albeit not significant) toward impaired water-maze memory.…”

“…This apparent divergence may signify that the higher retention of memories in MAO-deficient mice can only be observed during the processing of emotional memories. The enhanced fear in MAO A/B KO mice could result from elevated monoamine levels in the amygdala (12,(19)(20)(21)(22). Enhanced amygdaloid functioning in MAO A/B KO mice resulting from the presence of high levels of monoamines could also underlie our previous observation of increased anxiety and decreased social interactions in these animals (23)(24)(25).…”

“…Because MAO A/B KO mice showed significantly higher freezing in the new context, we compared the freezing during the third minute with that in the fourth minute (first minute of tone exposure). MAO A/B KO mice showed a more robust response to the tone [F (1,14) = 22.12 ; P < 0.001] compared with a similar analysis for WT mice [F (1,12) = 8.76; P < 0.01].…”

“…MAO A has a higher affinity for 5-HT, NE, and DA (6,10). In contrast, MAO B prefers phenylethylamine (PEA) as substrate (11), although it can degrade 5-HT, NE, and DA in the absence of MAO A (12). As a consequence, the lack of both isoenzymes in mice results in significantly higher monoamine levels than those observed in single knockout (KO) counterparts (12).…”

“…In contrast, MAO B prefers phenylethylamine (PEA) as substrate (11), although it can degrade 5-HT, NE, and DA in the absence of MAO A (12). As a consequence, the lack of both isoenzymes in mice results in significantly higher monoamine levels than those observed in single knockout (KO) counterparts (12). The deficiency of both MAO isoenzymes in humans has been found to be associated with severe intellectual and developmental disabilities, hypotonia, failure to thrive, and autisticlike symptoms (including sociocommunicative deficits and perseverative manifestations) (13)(14)(15).…”