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Serotonin receptor 2A (HTR2A) and 1A (HTR1A) signaling in rat cortical neurons and lymphocytes from children and adolescents with early-onset obsessive-compulsive disorder: role of histone deacetylase inhibition and receptor polymorphism.

Applicant Marinova Zoya
Number 134106
Funding scheme Marie Heim-Voegtlin grants
Research institution Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurology, Psychiatry
Start/End 01.02.2011 - 31.01.2013
Approved amount 194'273.00
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Keywords (7)

early-onset obsessive-compulsive disorder; serotonin; HTR2A polymorphism; histone deacetylase inhibition; histone methylation; HTR1A; child and adolescent psychiatry

Lay Summary (English)

Lead
Lay summary
Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent, intrusive thoughts (obsessions) and repetitive behaviors (compulsions). It affects 1-3% of the population and can be very distressing to the patients and their families. Early?onset OCD starts before 18 years of age and has particularly high heritability. Changes in the neurotransmitter serotonin have been associated with OCD, as well as with depression. Two receptor subtypes that serotonin interacts with are the serotonin 2A and 1A receptors. Animal models have demonstrated that these receptor subtypes are critical for anxiety. Furthermore, they are targets for some current therapeutic agents for mental illness. A gene polymorphism (variant) of the serotonin 2A receptor called rs6311 has been associated with early?onset OCD, but its functional significance is still not clarified. Epigenetic changes are not directly altering the DNA sequence. They include acetylation and methylation of histone proteins, and can alter the transcriptional activity of genes. Epigenetic changes have been implicated in mental illness, but the information about their role in serotonin signaling is very limited. We will test the hypothesis that epigenetic modifications and the rs6311 receptor polymorphism influence serotonin signaling, focusing on serotonin 2A and 1A receptor subtypes. We aim to identify new downstream targets regulated by serotonin 2A and 1A receptors in rat cortical neurons and cell lines and determine the role of epigenetic changes on them. We will also test the rs6311 polymorphism effect on serotonin 2A receptor signaling in lymphocyte cultures from early?onset OCD patients and controls. We will further test whether this polymorphism affects histone modifications of the serotonin 2A receptor promoter and the effect of histone deacetylase inhibitors in lymphocytes from early?onset OCD and control subjects. We will use biochemical, molecular and cell biology methods to achieve these aims. We expect our results to enrich knowledge about serotonin 2A and 1A receptor signaling and the effect of epigenetic changes on it. Furthermore, we expect they will provide information about the functional significance of the rs6311 polymorphism in early?onset OCD. In a broader sense, the current study may help the identification of peripheral biomarkers for early?onset OCD and of new potential therapeutic targets.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Effects of oxytocin and arginine vasopressin on the proliferation and differentiation of a serotonergic cell line
Marinova Zoya, Walitza Susanne, Grünblatt Edna (2017), Effects of oxytocin and arginine vasopressin on the proliferation and differentiation of a serotonergic cell line, in Journal of Neural Transmission.
Real-time impedance-based cell analyzer as a tool to delineate molecular pathways involved in neurotoxicity and neuroprotection in neuronal cell line.
Marinova Zoya, Walitza Susanne, Grünblatt Edna (2014), Real-time impedance-based cell analyzer as a tool to delineate molecular pathways involved in neurotoxicity and neuroprotection in neuronal cell line., in Journal of Visualized Experiments, (90), e51748.
5-HT2A serotonin receptor agonist DOI alleviates cytotoxicity in neuroblastoma cells: Role of the ERK pathway
Marinova Zoya, Walitza Susanne, Grünblatt Edna (2013), 5-HT2A serotonin receptor agonist DOI alleviates cytotoxicity in neuroblastoma cells: Role of the ERK pathway, in Progress in Neuro-Psychopharmacology & Biological Psychiatry, 44, 64-72.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Tag der Forschung Psychiatrie sowie Kinder- und Jugendpsychiatrie Poster Signaling pathways regulated by the serotonin 2A receptor agonist DOI in neuronal cells 12.12.2012 Zürich, Switzerland Marinova Zoya;
SGKJPP Jahreskongress 2012 Talk given at a conference Serotonin 5-HT2A receptor signaling in a neuronal cell line involves activation of tyrosine kinases: implications for neuronal cell function. 30.08.2012 Zürich, Switzerland Marinova Zoya;
8th FENS Forum of Neuroscience Poster 5-HT2A SEROTONIN RECEPTOR AGONIST DOI PROTECTS NEUROBLASTOMA CELLS AGAINST SERUM DEPRIVATION-INDUCED TOXICITY: INVOLVEMENT OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE PATHWAY 14.07.2012 Barcelona, Spain, Spain Marinova Zoya;
NCCR NEURO CONCLUDING SYMPOSIUM & ZNZ SYMPOSIUM Poster Cell culture models to investigate the signalling and interaction of serotonin 1A and 2A receptors 14.06.2012 Zürich, Switzerland Marinova Zoya;
Swiss Society for Neuroscience Annual Meeting 2012 Poster THE SEROTONIN 2A RECEPTOR FUNCTION ANALYSIS IN NEURONAL CELL CULTURE 03.02.2012 Zurich, Switzerland Marinova Zoya;
Tag der Forschung der Psychiatrie und Kinder- und Jugend Psychiatrie Poster THE SEROTONIN 2A RECEPTOR FUNCTION ANALYSIS IN NEURONAL CELL CULTURE 09.12.2011 Zurich, Switzerland Marinova Zoya;
5th meeting of the International College of Obsessive Compulsive Spectrum Disorders Poster The serotonin 2A receptor agonist DOI protects human neuroblastoma SK-N-SH cells against serum deprivation through tyrosine kinase activation 08.09.2011 Paris, France, France Marinova Zoya;


Associated projects

Number Title Start Funding scheme
130237 Neuroimaging of cognitive flexibility and action monitoring in paediatric obsessive-compulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD) 01.11.2010 Project funding (Div. I-III)
145697 Serotonin receptor 2A (HTR2A) and 1A (HTR1A) signaling in lymphocytes from patients with obsessive-compulsive disorder: role of epigenetic modifications and receptor polymorphism. 01.02.2013 Marie Heim-Voegtlin grants

Abstract

Serotonin signaling, including HTR2A and HTR1A, is implicated in obsessive-compulsive disorder (OCD) and depression. The HTR2A -1438G/A polymorphism was shown to be associated with early-onset OCD, but its functional significance is unclear. HTR1A can be functionally antagonistic to HTR2A and its deletion is associated with increased anxiety in mice. Furthermore, epigenetic modifications may affect serotonin signaling. We will test the hypothesis that epigenetic modifications and the -1438G/A HTR2A promoter polymorphism influence serotonin signaling, focusing on HTR2A and HTR1A. We aim to identify downstream targets regulated by HTR2A and HTR1A in rat cortical neurons and determine the role of histone deacetylase inhibition on them. We will also test the -1438G/A HTR2A polymorphism effect on HTR2A target molecules expression and on HTR2A promoter histone acetylation and methylation in lymphocyte cultures from early-onset OCD patients. We expect our results to enrich knowledge about dysregulation of serotonergic signaling and genetic vulnerability to early-onset OCD.
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