The objective of this application is to test the hypothesis that: 1) early developmental stages are critically important for monoamine oxidase (MAO) A to induce long-term effects on neuroplasticity and aggression through the regulation of serotonin (5-hydroxytryptamine, 5-HT) levels and the activation of 5-HT receptors in forebrain regions;and 2) environmental stress interacts with MAO A to modulate these processes. MAO A is the key enzyme in 5-HT metabolism, and its deficiency results in increased 5-HT levels and increased aggression in humans and mice. 5-HT in forebrain regions (frontal cortex, amygdala and hippocampus) modulates aggression as well as dendrite and spine morphology in pyramidal neurons.
The specific aims are outlined below: 1: To identify which early developmental stages are critical for the effects of 5-HT on aggression and dendritic morphology and spine density in pyramidal neurons of frontal cortex, amygdala and hippocampus in MAO A knockout (KO) mice. MAO A KO mice will be injected with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) during each of the 5 weeks of forebrain 5-HT innervation (E16-P28),to normalize the increased 5-HT levels in their forebrain regions. 5-HT levels will be determined by HPLC. Aggression and other related behaviors will be tested in adult mice (P60). Once we identify the critical stage for 5-HT role in behavior, we will study dendrite and spine morphology of 5-HT-targeted pyramidal neurons in forebrain regions, using light microscopy on Golgi-Cox stained brain sections as well as fluorescence microscopy on sections with 5-HT receptor labels and retrograde label of dendritic processes. 2: To identify what 5-HT receptors mediate the effects of 5-HT on aggression and dendritic morphology in forebrain regions of MAO A KO mice during the critical developmental stages. After treating MAO A KO mice with PCPA at the critical stages, we will quantify 5-HT1A, 5-HT1B and 5-HT2A receptors (mRNA levels) in their forebrain regions, by RT-PCR. To study the role of each receptor in behavior and morphology, we will inject MAO A KO mice with selective antagonists of specific 5-HT receptors during the specific critical stages, and determine which receptor blockade attenuates aggression and morphological alterations at P60. 3: To test the hypothesis that the interaction between MAO A and acute or chronic environmental stress induces specific changes in 5-HT in forebrain regions, which result in increased aggression and altered dendrite and spine morphology. We will study the impact of acute and chronic restraint stress on the behavior and brain morphology of MAO A KO mice. These studies will provide a significant contribution to basic and clinical research, by elucidating the impact of developmental mechanisms and stress on aggression, and shed light on new preventive and therapeutic strategies for aggression and other psychiatric disorders, including alcohol and drug abuse.

Public Health Relevance

This application will study the role of monoamine oxidase (MAO) A during critical developmental stages and in specific forebrain regions on the regulation of serotonin levels, brain morphology and aggressive and related emotional behaviors. The interaction between MAO A and environmental stress and its impact on these phenomena will also be studied. This research will provide critically important findings for the understanding of the molecular bases and the brain circuitry of aggression. It will also shed new light on preventive, diagnostic and therapeutic strategies for aggression and other mental disorders associated with abnormal monoamine neurotransmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH039085-27
Application #
8196826
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
1985-09-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
27
Fiscal Year
2012
Total Cost
$398,228
Indirect Cost
$138,105
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Godar, Sean C; Bortolato, Marco; Richards, Sarah E et al. (2015) Monoamine Oxidase A is Required for Rapid Dendritic Remodeling in Response to Stress. Int J Neuropsychopharmacol 18:
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Godar, Sean C; Bortolato, Marco; Castelli, M Paola et al. (2014) The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake. J Psychiatr Res 56:1-9
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Singh, Chanpreet; Bortolato, Marco; Bali, Namrata et al. (2013) Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice. Proc Natl Acad Sci U S A 110:12816-21
Bortolato, Marco; Godar, Sean C; Tambaro, Simone et al. (2013) Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice. Neuropharmacology 75:223-32
Alzghoul, Loai; Bortolato, Marco; Delis, Foteini et al. (2012) Altered cerebellar organization and function in monoamine oxidase A hypomorphic mice. Neuropharmacology 63:1208-17
O'Leary, Ryan E; Shih, Jean C; Hyland, Keith et al. (2012) De novo microdeletion of Xp11.3 exclusively encompassing the monoamine oxidase A and B genes in a male infant with episodic hypotonia: a genomics approach to personalized medicine. Eur J Med Genet 55:349-53

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