Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice

Abstract

Monoamine oxidase (MAO) A, the major enzyme catalyzing the oxidative degradation of serotonin (5-hydroxytryptamine, 5-HT), plays a key role in emotional regulation. In humans and mice, MAO-A deficiency results in high 5-HT levels, antisocial, aggressive, and perseverative behaviors. We previously showed that the elevation in brain 5-HT levels in MAO-A knockout (KO) mice is particularly marked during the first two weeks of postnatal life. Building on this finding, we hypothesized that the reduction of 5-HT levels during these early stages may lead to enduring attenuations of the aggression and other behavioral aberrances observed in MAO-A KO mice. To test this possibility, MAO-A KO mice were treated with daily injections of a 5-HT synthesis blocker, the tryptophan hydroxylase inhibitor p-chloro-phenylalanine (pCPA, 300 mg/kg/day, IP), from postnatal day 1 through 7. As expected, this regimen significantly reduced 5-HT forebrain levels in MAO-A KO pups. These neurochemical changes persisted throughout adulthood, and resulted in significant reductions in marble-burying behavior, as well as increases in spontaneous alternations within a T-maze. Conversely, pCPA-treated MAO-A KO mice did not exhibit significant changes in anxiety-like behaviors in a novel open-field and elevated plus-maze; furthermore, this regimen did not modify their social deficits, aggressive behaviors and impairments in tactile sensitivity. Treatment with pCPA from postnatal day 8 through 14 elicited similar, yet milder, behavioral effects on marble-burying behavior. These results suggest that early developmental enhancements in 5-HT levels have long-term effects on the modulation of behavioral flexibility associated with MAO-A deficiency.

Keywords: Aggression; Animal models; Early developmental stages; Monoamine oxidase A; Perseverative behaviors; Serotonin.

Figure 1

Schematic representation of the experimental design for pCPA administration during the first two postnatal weeks. Behavioral analyses were performed between postnatal day 90 and postnatal day 120 (corresponding to adulthood).

Figure 2

Effects of pCPA treatment from postnatal day 1 through 7 on open-field behaviors in adult wild type (WT) and MAO-A KO mice. Values are represented as mean ± SEM. ^P<0.05; ^^^P<0.001 compared to WT mice (main effect of genotype). Main effects of treatment are not indicated. For more details, see text.

Figure 3

Effects of pCPA treatment from postnatal day 1 through 7 on elevated-plus maze behaviors in adult wild type (WT) and MAO-A KO mice. Values are represented as mean ± SEM. ^P<0.05; ^^^P<0.001 compared to WT mice (main effect of genotype). ^†P<0.05 compared to MAO-A KO mice treated with saline. For more details, see text.

Figure 4

Effects of pCPA treatment from postnatal day 1 through 7 on the proclivity of adult wild type (WT) and MAO-A KO mice to explore a novel object in their home cage. Values are represented as mean ± SEM. *P<0.05; **P<0.01; ***P<0.001, compared to untreated WT mice. ^#P<0.05; ^###P<0.001, compared to untreated MAO-A-deficient mice; ^†P<0.05, compared to saline-treated MAO-A KO mice. For more details, see text.

Figure 5

Effects of pCPA treatment from postnatal day 1 through 7 on A) marble-burying behavior and B) spontaneous alternations in a T-maze of adult wild type (WT) and MAO-A KO mice. Values are represented as mean ± SEM. *P<0.05; ***P<0.001, compared to untreated WT mice. ^#P<0.05; ^###P<0.001, compared to untreated MAO-A-deficient mice; ^†P<0.05; ^††P<0.01 compared to saline-treated MAO-A KO mice. For more details, see text.

Figure 6

Effects of pCPA treatment from postnatal day 1 through 7 on A-B) social interaction and C-D) resident-intruder aggression in adult wild type (WT) and MAO-A KO mice. Values are represented as mean ± SEM. ^^^P<0.001 compared to WT mice (main effect of genotype). For more details, see text.

Figure 7

Effects of pCPA treatment from postnatal day 1 through 7 on the latencies to A) remove a sticky tape from the paws and B) lick paws in the hot plate test of adult wild type (WT) and MAO-A KO mice. Values are represented as mean ± SEM. ^P<0.05; ^^^P<0.001 compared to WT mice (main effect of genotype). For more details, see text.

Figure 8

Effects of pCPA treatment from postnatal day 8 through 14 on A) marble-burying behavior, B-C) novel-object exploration; and D-E) resident-intruder responses of adult wild type (WT) and MAO-A KO mice. Values are represented as mean ± SEM. ^P<0.05; ^^^P<0.001 compared to WT mice (main effect of genotype); *P<0.05; ***P<0.001, compared to untreated WT mice. ^#P<0.05; ^##P<0.01, compared to untreated MAO-A-deficient mice. Main effects of treatment are not indicated. For more details, see text.