Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A

Abstract

The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic Tg8 mice on the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) biosynthesis, and on the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain, hypothalamus, hippocampus, striatum, amygdala, and frontal cortex was studied. It was shown that mice with a genetic MAO A knockout differed from mice of the initial C3H/HeJ strain in having a higher level of 5-HT and a lower level of its metabolite, 5-HIAA, in all brain regions but the frontal cortex, where the changes were insignificant. Although the 5-HIAA/5-HT ratio in various brain regions differed considerably, the decrease of the 5-HT oxidative deamination index in Tg8 mice was similar in different brain regions (to 41-45% of control values), with the exception of the frontal cortex, where the decrease of the 5-HIAA/5-HT was somewhat smaller (to 54%). The presence of the remaining 45% +/- 1.9% of the control ratio value indicates rather effective oxidative deamination of 5-HT in MAO A knockout mice and explains the lack of severe behavioral and pathological consequences in MAO A genetic deficiency. An increase of TPH activity in mice lacking MAO A was found in the frontal cortex, hippocampus, and amygdala. No significant changes were found in the striatum, hypothalamus, and midbrain. The data show an effect of the MAO A gene mutation on TPH and indicate a uniform decrease of 5-HT catabolism in different brain regions except for the frontal cortex, which is somewhat more resistant to the lack of MAO A than other brain structures.

From genes to aggressive behavior: the role of serotonergic system

“…Indeed, some years ago, a Dutch family with a point mutation in the 8 th exon of the structural MAO A gene was found by Brunner et al (49) Four generations of this large kindred were examined, and 14 affected men with a complex behavioral syndrome characterized by borderline mental retardation and behavioral abnormalities with impulsive aggression were described. (50) In MAO Adeficient mice, changes in the level of catecholamines, 5-HT and their metabolites, as well as in aggressiveness (43,45) are similar to those found in the Dutch family. (49,50) It is interesting to note that the association of a regulatory polymorphism in the promoter region of the MAO A gene with antisocial alcoholism in 303 alcohol-dependent German descent male subjects including 59 alcoholics with antisocial personality disorder was described.…”

“…(45) Taken together, the evidence reviewed above suggests that 5-HT 1A receptors in the limbic system of the brain may fulfill a significant role in the expression of aggressiveness, and inherited high or low aggressiveness may be determined, at least partly, by the expression and density of 5-HT 1A receptors in the limbic system.…”

“…(43,44) Tg8 mice have been found to lack brain MAO A activity and to have elevated 5-HT levels and lowered concentrations of the main 5-HT metabolite, 5-HIAA. (43,45) In MAO A-deficient mice, there was a significant decrease in the 5-HIAA/5-HT ratio in the brain regions. (45) Despite the pronounced differences between various brain regions in this value, the relative 5-HIAA/5-HT ratio decrease in Tg8 mice versus the control C3H strain was surprisingly similar (to 45%) in all six brain structures studied.…”

“…(43,45) In MAO A-deficient mice, there was a significant decrease in the 5-HIAA/5-HT ratio in the brain regions. (45) Despite the pronounced differences between various brain regions in this value, the relative 5-HIAA/5-HT ratio decrease in Tg8 mice versus the control C3H strain was surprisingly similar (to 45%) in all six brain structures studied. A lowered 5-HIAA level and 5-HIAA/5-HTratio suggested a decreased functional activity of the 5-HT system in the brain of Tg8 mice.…”

The domestication and the brain: forty years after

“…Проблема осложняется тем, что изменение экспрессии любого из ключевых генов, контролирующих серотони-новую систему, нарушает ее функционирование и может повлиять на агрессивность. Так, более агрессивны мыши с нокаутом МАО А (Cases et al, 1995;Popova et al, 2001) и мужчины -носители однолокусной мутации МАО А (Brunner, 1995). Нокаут гена, контролирующего транспор-тер серотонина, понижает агрессивность мышей (Holmes et al, 2002).…”