title: Monoamine oxidases regulate telencephalic neural progenitors in late embryonic and early postnatal development.
abstract: Monoamine neurotransmitters play major roles in regulating a range of brain functions in adults and increasing evidence suggests roles for monoamines in brain development. Here we show that mice lacking the monoamine metabolic enzymes MAO A and MAO B (MAO AB-deficient mice) exhibit diminished proliferation of neural stem cells (NSC) in the developing telencephalon beginning in late gestation [embryonic day (E) 17.5], a deficit that persists in neonatal and adult mice. These mice showed significantly increased monoamine levels and anxiety-like behaviors as adults. Assessments of markers of intermediate progenitor cells (IPC) and mitosis showed that NSC in the subventricular zone (SVZ), but not in the ventricular zone, are reduced in MAO AB-deficient mice. A developmental time course of monoamines in frontal cortical tissues revealed increased serotonin levels as early as E14.5, and a further large increase was found between E17.5 and postnatal day 2. Administration of an inhibitor of serotonin synthesis (parachlorophenylalanine) between E14.5 and E19.5 restored the IPC numbers and SVZ thickness, suggesting the role of serotonin in the suppression of IPC proliferation. Studies of neurosphere cultures prepared from the telencephalon at different embryonic and postnatal ages showed that serotonin stimulates proliferation in wild-type, but not in MAO AB-deficient, NSC. Together, these results suggest that a MAO-dependent long-lasting alteration in the proliferation capacity of NSC occurs late in embryonic development and is mediated by serotonin. Our findings reveal novel roles for MAOs and serotonin in the regulation of IPC proliferation in the developing brain.
authors: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
authors: Aiwu
authors: A
authors: Cheng
authors: Anna L
authors: AL
authors: Scott
authors: Bruce
authors: B
authors: Ladenheim
authors: Kevin
authors: K
authors: Chen
authors: Xin
authors: X
authors: Ouyang
authors: Justin D
authors: JD
authors: Lathia
authors: Mohamed
authors: M
authors: Mughal
authors: Jean Lud
authors: JL
authors: Cadet
authors: Mark P
authors: MP
authors: Mattson
authors: Jean C
authors: JC
authors: Shih
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015306:Biogenic Monoamines / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology; D004622:Embryo, Mammalian; D010134:Fenclonine / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013234:Stem Cells / Q000502:physiology*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology / Q000254:growth & development
chemical_list: D015306:Biogenic Monoamines; D012702:Serotonin Antagonists; D008995:Monoamine Oxidase; D001973:Bromodeoxyuridine; D010134:Fenclonine