Monoamine oxidase deficiency and emotional reactivity: Neurochemical and developmental studies.

摘要

Monoamine oxidases (MAOs) serve a crucial function in the regulation of mood and behavior. The two isoenzymes, MAO A and MAO B, are expressed in a variety of brain and peripheral tissues where they catalyze the oxidative deamination of neurotransmitter and dietary monoamines. MAO A preferentially catabolizes serotonin (5-HT) and norepinephrine (NE), MAO B prefers the trace amine phenylethylamine (PEA), and both catabolize dopamine (DA). In the absence of MAO A, MAO B oxidizes MAO A's preferred substrates and vice versa, indicating partial functional redundancy.;Despite a wealth of evidence demonstrating that MAO mutations result in deficient monoamine metabolism and maladaptive emotional reactivity, the specific mechanisms underpinning this relationship remain highly elusive. Studies included in this dissertation begin to fill this gap. This work has focused on MAO A and dual MAO A/B mutations that result in deficient metabolism of 5-HT and NE. Knock out (KO) mice harboring these mutations were evaluated using behavioral paradigms designed to explore different facets of emotional responsiveness. These studies were carried out in conjunction with biochemical and cellular assays to elucidate factors that contribute to the emotional impairments exhibited by these lines. Collectively, these studies enhance our understanding of the behavioral phenotypes displayed by MAO A KO and MAO A/B KO mice and highlight novel neurochemical and developmental perturbations which may have a causal role in the emotional disturbances displayed by these lines.;This dissertation (1) Describes a novel line of mice harboring a human-like mutation in MAOA analogous to the cause of a rare disorder featuring impulsive aggressiveness; (2) Provides strong evidence that the phenotype associated with total MAO deficiency features a general dysregyulation in the emotional processing of environmental cues; (3) Highlights nitric oxide as an interesting substrate for certain behavioral disturbances in MAO A KO and MAO A/B KO mice and (4) Defines novel roles for MAOs and 5-HT during embryonic and early postnatal stages of development. Collectively, this work provides new models and mechanisms to understand the consequences of MAO deficiency on the regulation of emotional behaviors.