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dc.contributor.advisorAndrés-Coke, María Estela
dc.creatorOlivares-Costa, Montserrat
dc.description.abstractImmediate Early genes (IEGs) are fast and transiently induced after neuronal stimulation, and their function is closely related to synaptic plasticity and gene expression regulation. The IEG, NR4A1 (Nur77) is a transcription factor highly modulated by dopaminergic transmission and is related to diseases characterized by imbalances in dopamine system, such as stress, anxiety, addiction, and schizophrenia. However, mechanisms modulating its expression are not fully described as well as their specific function in neurons. Here we propose the epigenetic enzyme, Lysine-Specific Demethylase 1 (LSD1, KDM1A) as modulator of the NR4A1 expression. LSD1 has a neuronal specific variant, neuroLSD1, that is necessary for neuronal differentiation and participates in processes such as memory, learning, and stress response. Mice null for neuroLSD1 are less prone to develop anxious behavior, associated with lower induction of IEGs compared to wild type littermates. All the aforementioned data lead us to propose LSD1 as an effector of the molecular and behavioral dopamine-mediated response. Our data suggest that signaling through D2 dopamine receptors regulates LSD1 and neuroLSD1 expression. Acute and repeated administration of amphetamine induce transient and long-term effects on LSD1 levels, revealing a negative feedback regulation exerted by neuroLSD1. Neurochemical and locomotor characterization of neuroLSD1 null mice show decreased dopamine release but similar locomotor sensitization when treated with amphetamine compared to wild-type mice. Our data also show that both LSD1 and neuroLSD1 increase the activity of the NR4A1 promoter. By bicuculline treatment of cultured hippocampal neurons from neuroLSD1 null mice, we rule out that neuroLSD1 is essential for IEGs expression. Our data suggest that the phosphorylation of a neuroLSD1-specific threonine conform an on/off switch for IEGs transcription. In conclusion, we show than LSD1 and neuroLSD1 are readers of dopamine synaptic levels and modulate the expression of the dopamine related IEG NR4A1. Finally, we use available data bases to identify NR4A1 target genes in an effort to unveil its function.es_CL
dc.relationinstname: Conicyt
dc.relationreponame: Repositorio Digital RI2.0
dc.titleuLSD1/neuroLSD1 ratio is a molecular sensor of dopaminergic transmission and a regulator of the immediate-early gene Nur77es_CL
dc.subject.oecd1nCiencias Naturaleses_CL
dc.subject.oecd2nOtras Ciencias Naturaleses_CL

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