From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency

Abstract

The two monoamine oxidase (MAO) enzymes, A and B, catalyze the metabolism of monoamine neurotransmitters, such as serotonin, norepinephrine, and dopamine. The phenotypic outcomes of MAO congenital deficiency have been studied in humans and animal models, to explore the role of these enzymes in behavioral regulation. The clinical condition caused by MAOA deficiency, Brunner syndrome, was first described as a disorder characterized by overt antisocial and aggressive conduct. Building on this discovery, subsequent studies were focused on the characterization of the role of MAOA in the neurobiology of antisocial conduct. MAO A knockout mice were found to display high levels of intermale aggression; however, further analyses of these mutants unveiled additional behavioral abnormalities mimicking the core symptoms of autism-spectrum disorder. These findings were strikingly confirmed in newly reported cases of Brunner syndrome. The role of MAOB in behavioral regulation remains less well-understood, even though Maob-deficient mice have been found to exhibit greater behavioral disinhibition and risk-taking responses, supporting previous clinical studies showing associations between low MAO B activity and impulsivity. Furthermore, lack of MAOB was found to exacerbate the severity of psychopathological deficits induced by concurrent MAOA deficiency. Here, we summarize how the convergence of clinical reports and behavioral phenotyping in mutant mice has helped frame a complex picture of psychopathological features in MAO-deficient individuals, which encompass a broad spectrum of neurodevelopmental problems. This emerging knowledge poses novel conceptual challenges towards the identification of the endophenotypes shared by autism-spectrum disorder, antisocial behavior and impulse-control problems, as well as their monoaminergic underpinnings.

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation

“…These phenotypes are highly reminiscent of the deficits observed in MAOA knockout pups (Cases et al, 1995;Bortolato et al, 2013a), further highlighting the importance of this enzyme in early developmental stages. According, recent clinical evidence has shown developmental delays in boys harboring nonsense MAOA mutations (Bortolato et al, 2018). Interestingly, antisocial and externalizing tendencies in children are associated with hyperactivity (Barkley et al, 2004), low body weight (Cimino et al, 2016), and communication deficits (Petersen et al, 2013); in view of this background, our findings raise the intriguing possibility that these associations may be moderated by low-activity MAOA alleles.…”

A Rat Model of Human Behavior Provides Evidence of Natural Selection Against Underexpression of Aggressiveness-Related Genes in Humans

“…By contrast, overexpression of Comp reduces aggressiveness (Wilhelm et al, 2013), whereas either overexpression or underexpression of 5HTT, depending on the brain region, can either weaken or enhance this trait (Kudryavtseva et al, 2017). Underexpression of genes Maoa (Bortolato et al, 2018) and Drd4 (Keck et al, 2013) can increase it. Consequently, these genes well known for their association with aggressiveness cannot be in our set of analyzed genes (see "Study Design" subsection).…”

2‐Phenyloxazole‐4‐carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

“…[2,3] Being involved in the catabolism of neurotransmitters, MAOs are established pharmacological targets for various neurological, psychiatric, and neurodegenerative diseases. [4][5][6] Indeed, MAO inhibitors lower the catabolism of neurotransmitters, with ac oncomitantd ecrease in the generation of corresponding aldehydes,a mmonia,a nd hydrogen peroxide (reaction products), which, ath igh concentrations, may be toxic and are linked to conditions of oxidative stress, which is the basis of variouspathologies.…”