Monoamine Oxidases Regulate Telencephalic Neural Progenitors in Late Embryonic and Early Postnatal Development

Cheng, Ann‐Lii; Scott, Anna L.; Ladenheim, Bruce; Chen, Kevin; Ouyang, Xin; Lathia, Justin D.; Mughal, Mohamed R.; Cadet, Jean Lud; Mattson, Mark P.; Shih, Jean C.

doi:10.1523/jneurosci.2037-10.2010

Cited by 43 publications

(55 citation statements)

References 69 publications

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“…*, p Ͻ 0.01. cal results. In fact, recent observations of impaired cell proliferation of the telencephalon during late embryo development in an MAO-A/B-deficient mouse line supports our line of argumentation that MAO-A affects prenatal development (32).…”

Section: Discussionsupporting

confidence: 82%

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Wang

Borchert

Ugun-Klusek

et al. 2011

Journal of Biological Chemistry

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Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression R1 was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium, which coincided with impaired activation of caspases 3 and 9. Moreover, we observed reduced cyclin D1 levels as an indicator of impaired cell proliferation in MAO-A knockdown embryos. This data highlights MAO-A as a vital regulator of embryonic brain development.

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Section: Discussionsupporting

confidence: 82%

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Wang

Borchert

Ugun-Klusek

et al. 2011

Journal of Biological Chemistry

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“…The enhancement in adult neurogenesis challenges the possibility that a deficit in context discrimination contributed to overgeneralized fear. Surprisingly, the increase in adult neurogenesis contrasts with our previous observations (18,31), where we showed a diminished proliferation of neural stem cells in the developing and adult subventricular zone (18) in MAO A/B KO mice and reduced differentiation of neural cells in MAO A KO embryonic stem cell lines (31). This indicates that the regulation of neurogenesis in these two regions is very different (e.g., multiple receptor subtypes mediate the potent, partly selective of each neurogenic zone, stimulatory action of 5-HT on adult brain cell proliferation) (32).…”

Section: Mao A/b Ko Mice Showed Enhanced Contextual and Cue Memory Andcontrasting

confidence: 99%

“…In addition, we found an increased adult hippocampal neurogenesis in MAO A/B KO mice. The present results complement and extend previous findings from our group and others on the characterization of the phenotypic consequences of combined MAO A and MAO B deficiency in humans and mice (12,(14)(15)(16)18). MAO A/B KO mice exhibited a statistical trend (albeit not significant) toward impaired water-maze memory.…”

Section: Mao A/b Ko Mice Showed Enhanced Contextual and Cue Memory Andsupporting

confidence: 91%

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Singh

Bortolato

Bali

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.adult neurogenesis | autism-spectrum disorder | cognition M onoaminergic neurotransmitters, such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), are known to play a critical role in the modulation of mood and emotion, as well as the control of motor, perceptual, and other cognitive functions (1). Abnormal levels of these monoamines have been associated with several neuropsychiatric disorders (2-5). The enzymatic metabolism of these neurotransmitters is mainly catalyzed by monoamine oxidase (MAO), a mitochondrial-bound flavoprotein (6). The two MAO isoenzymes, A and B, are encoded by different genes next to each other on the X chromosome (7), with 70% amino acid identity (8) and identical intron-exon organization (9). MAO A has a higher affinity for 5-HT, NE, and DA (6, 10). In contrast, MAO B prefers phenylethylamine (PEA) as substrate (11), although it can degrade 5-HT, NE, and DA in the absence of MAO A (12). As a consequence, the lack of both isoenzymes in mice results in significantly higher monoamine levels than those observed in single knockout (KO) counterparts (12). The deficiency of both MAO isoenzymes in humans has been found to be associated with severe intellectual and developmental disabilities, hypotonia, failure to thrive, and autisticlike symptoms (including sociocommunicative deficits and perseverative manifestations) (13-15). Although similar alterations were also featured by MAO A KO mice, the severity of the changes was typically more pervasive in MAO A/B KO mice, supporting the idea that the se...

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“…The analysis of mice lacking MAOA and B, which displays high 5-HT levels but normal dopamine and norepinephrine levels during development, revealed a specific reduction of symmetric divisions of intermediate precursors cells [76] in SVZ during late corticogenesis (E17.5) [182]. This unexpected alteration was reverted after pharmacological inhibition of 5-HT synthesis (with p-chlorophenylalanine; PCPA) between E14.5-E19.5.…”

Section: Serotonin and Cell Proliferationmentioning

confidence: 99%

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

Vitalis¹,

Verney²

2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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The mammalian cerebral cortex is critical for sensory and motor integrations and, for higher-order cognitive functions. The construction of mammalian cortical circuits involves the coordinated interplay between cellular processes such as proliferation, migration and differentiation of neural and glial cell subtypes followed by accurate connectivity evolving in complexity in primates. Alteration in cortical development may induce the emergence of various pathological traits and behaviours. Among the large array of factors that regulate the assembly of cortical circuits, serotonin (5-HT) plays important role as a developmental signal that impacts on a broad diversity of cellular processes. 5-HT plays distinct roles during specific sensitive periods and is produced from various sources depending on the perinatal stage. Its roles are mediated by more than fourteen 5-HT receptors that are all G-protein coupled receptors except the ionotropic 5-HT type 3A receptor (5-HT 3A ) mediating rapid neuronal activation. Importantly, 5-HT metabolism and signalling are influenced by numerous epigenetic and genetic factors, including nutrition and gut microbiota, perinatal stress, infection and inflammation. In this review, we will recapitulate some evidences showing that dysregulation of 5-HT homeostasis and 5-HT 3A signalling impairs distinct steps of cortical circuit formation leading to the predisposition of the onset of various psychiatric diseases.

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Monoamine Oxidases Regulate Telencephalic Neural Progenitors in Late Embryonic and Early Postnatal Development

Cited by 43 publications

References 69 publications

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis

Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Sculpting Cerebral Cortex with Serotonin in Rodent and Primate

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