Forebrain-specific Expression of Monoamine Oxidase A Reduces Neurotransmitter Levels, Restores the Brain Structure, and Rescues Aggressive Behavior in Monoamine Oxidase A-deficient Mice

Abstract

Previous studies have established that abrogation of monoamine oxidase (MAO) A expression leads to a neurochemical, morphological, and behavioral specific phenotype with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults. Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase II␣ (CaMKII␣). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively. Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice. Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyindoleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice. These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice. This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype. Furthermore, the disorganization of the somatosensory cortex barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes.This study shows that a forebrain-specific expression of monoamine oxidase (MAO) 3 A is able to restore the disorganized somatosensory cortex barrel field structure and an aggressive behavior seen in MAO A KO mice. MAO A and B are outer membrane mitochondrial enzymes responsible for the metabolic degradation of biogenic amines in humans (1, 2). MAO A prefers serotonin (5-HT) and norepinephrine (NE) as substrates, whereas MAO B prefers phenylethylamine (PEA) and benzylamine (1-5). Dopamine (DA), tyramine, and tryptamine are common substrates for both forms. MAO A and B are encoded by different genes (6, 7) closely linked on the X chromosome (8). Both isoenzymes are widely present in most brain regions (9). MAO A gene deficiency in a Dutch family shows borderline mental retardation and impulsive aggression (10, 11). A promoter region was associated with high or low MAO A promoter activity (12). Individuals with low MAO A promoter activity who are maltreated in early childhood have increased risk for antisocial behavior as adults (13,14). These results indicated that the interaction of the gene and the environment of early childhood predispose the adult behavior. Functional magnetic resonance imaging in healthy human volunteers shows that the low expression variant, associated with increased risk of violent behavior, correlated with pronounced limbic volume reductions, hyper-responsive amygdala during emotional arousal, and diminished reactivity of r...

Social Deficits and Perseverative Behaviors, but not Overt Aggression, in MAO-A Hypomorphic Mice

“…In contrast with our previous findings on the C3H line of MAO-A KO mice (Tg8) (Chen et al, 2007), we did not detect any significant variation in 5-HT levels in the striatum of either MAO-A Neo or MAO-A KO mice in the 129S6 background; this variation may be related to the abundant MAO-B activity in the striatum of this strain , which may be able to offset some of the neurochemical outcomes of MAO-A deficiency.…”

“…These findings are in line with previous evidence showing that only relatively small amounts of MAO-A are required to sustain the homeostasis of 5-HT neurotransmission in the brain (Chen et al, 2007). Of note, NE levels were significantly higher than those observed in WT mice in both regions (although the amygdalar content of this monoamine was still significantly lower than its MAO-A KO counterpart).…”

“…saline solution) (10 mg/kg; injection volume: 10 ml/kg) or saline. MAO-A activity was determined as described previously (Chen et al, 2007;Grimsby et al, 1997), by incubation with radiolabeled 5-HT. (1) The 9.0-kb MAO-A BamHI fragment composed of a 6.7-kb BamHI-BglII and a 2.0-kb EcoRI-BamHI fragment.…”

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

“…Although the underlying mechanisms have not been studied in detail, these effects could be explained by the inability of the animals to metabolize serotonin (20). This data is consistent with the recent observation that transgenic overexpression of MAO-A in the forebrain of MAO-A knockout mice rescues their aggressive behavior (21).…”

Monoamine Oxidases: From Tissue Homogenates to Transgenic Mice

“…This rescued the neurotransmitter levels and the aggressive phenotype seen in MAO A KO. Specific neurological anatomical structures of the forebrain, the barrel fields which are lost upon MAO A KO, were also re-established and were visible via immunohistochemistry with this forebrain knockin [37].…”