Maladaptive defensive behaviours in monoamine oxidase A-deficient mice

Abstract

Rich evidence indicates that monoamine oxidase (MAO) A, the major enzyme catalysing the degradation of monoamine neurotransmitters, plays a key role in emotional regulation. Although MAOA deficiency is associated with reactive aggression in humans and mice, the involvement of this enzyme in defensive behaviour remains controversial and poorly understood. To address this issue, we tested MAOA knockout (KO) mice in a spectrum of paradigms and settings associated with variable degrees of threat. The presentation of novel inanimate objects induced a significant reduction in exploratory approaches and increase in defensive behaviours, such as tail-rattling, biting and digging. These neophobic responses were context-dependent and particularly marked in the home cage. In the elevated plus- and T-mazes, MAOA KO mice and wild-type (WT) littermates displayed equivalent locomotor activity and time in closed and open arms; however, MAOA KO mice featured significant reductions in risk assessment, as well as unconditioned avoidance and escape. No differences between genotypes were observed in the defensive withdrawal and emergence test. Conversely, MAOA KO mice exhibited a dramatic reduction of defensive and fear-related behaviours in the presence of predator-related cues, such as predator urine or an anaesthetized rat, in comparison with those observed in their WT littermates. The behavioural abnormalities in MAOA KO mice were not paralleled by overt alterations in sensory and microvibrissal functions. Collectively, these results suggest that MAOA deficiency leads to a general inability to appropriately assess contextual risk and attune defensive and emotional responses to environmental cues.

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

“…These transgenic animals show a number of aberrant phenotypes, including high brain concentrations of 5-HT and NE, and dysmorphic barrel fields. Importantly, male MAO-A KO mice show a number of behavioral disturbances strikingly similar to those observed in Brunner syndrome patients, including marked reactive aggression toward conspecifics and a distinct inability to attune their defensive responses to different contextual cues (Cases et al, 1995;Godar et al, 2010;Scott et al, 2008).…”

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study

“…For example, in addition to manifesting extreme impulsive aggression (Cases et al, 1995;Godar et al, 2011;Popova et al, 2001;Scott et al, 2008), MAO-A knockouts also exhibit cognitive and physiological responses characteristic of ASPD with high psychopathic traits, such as decreased startle reflex (Popova et al, 2001), reduced anxiety (Popova et al, 2001), impaired risk assessment (Godar et al, 2011), and attenuated stress reaction (Popova et al, 2006). While there are several manipulations that can lead to impulsive-aggressive behavior in rodents, a critical issue is whether such models actually translate to the human clinical phenotype.…”

Monoamine-Sensitive Developmental Periods Impacting Adult Emotional and Cognitive Behaviors

“…For example, unlike the anxiolytic effects of pharmacologic MAOA inhibition in adulthood, constitutive loss-of-function mutations of MAOA result in a syndrome characterized by antisocial/ aggressive behavior in humans (Brunner et al, 1993). Consistently, mice with genetic inactivation of MAOA (MAOA À / À ) exhibit not only neophobia but also heightened levels of aggression (Cases et al, 1995;Godar et al, 2010;Scott et al, 2008). The divergent effects of genetic (lifelong) mutations versus pharmacologic inhibition (during adulthood) suggest that perturbed monoamine signaling during sensitive periods of brain maturation differentially modulates adult aggression.…”