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Free keywords:
Adenine/metabolism
Animals
Cocaine/pharmacology
Corpus Striatum/physiology
Dopamine/*physiology
Dopaminergic Neurons/*enzymology/physiology
Exploratory Behavior/drug effects/physiology
Female
G Protein-Coupled Inwardly-Rectifying Potassium Channels/physiology
Locomotion/drug effects/physiology
Male
Mesencephalon/*physiology
Methylation
Methyltransferases/metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mixed Function Oxygenases/deficiency/genetics/*physiology
Oxo-Acid-Lyases/deficiency/genetics/*physiology
Phenotype
Quinpirole/pharmacology
RNA Processing, Post-Transcriptional
RNA, Messenger/metabolism
Receptors, Dopamine D2/deficiency/physiology
Receptors, Dopamine D3/physiology
Reward
Signal Transduction/drug effects
Abstract:
Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.
