Fluoxetine Modulates the Activity of Hypothalamic POMC Neurons via mTOR Signaling
Hypothalamic proopiomelanocortin (POMC) neurons are important players in the regulation of energy homeostasis; we previously demonstrated that environmental stimulation excites arcuate nucleus circuits to undergo plastic remodeling, leading to altered ratio between excitatory and inhibitory synaptic contacts on these neurons. The widely used selective serotonin reuptake inhibitor fluoxetine (FLX) is known to affect body weight. On the other hand, FLX administration mimics the effects of environmental stimulation on synaptic plasticity in the hippocampus and cortex. The mammalian target of rapamycin (mTOR) pathway is instrumental in these phenomena. Thus, we aimed at investigating whether and how FLX affects POMC neurons activity and hypothalamic mTOR function. Adult mice expressing green fluorescent protein (GFP) under the POMC promoter were treated with FLX for 3 weeks resulting in diminished body weight. Patch clamp recordings performed on POMC neurons indicate that FLX increases their firing rate and the excitatory AMPA-mediated transmission, and reduces the inhibitory GABAergic currents at presynaptic level. Immunofluorescence studies indicate that FLX increases the ratio between excitatory and inhibitory synaptic contacts on POMC neurons. These changes are associated with an increased activity of the hypothalamic mTOR pathway. Use of the mTOR inhibitor rapamycin blunts the effects of FLX on body weight and on functional and structural plasticity of POMC neurons. Our findings indicate that FLX is able to remodel POMC neurons, and that this may be partly mediated by the mTOR signaling pathway.
KeywordsFluoxetine Hypothalamus POMC neurons Patch clamp Plasticity mTOR pathway
We want to thank Jeffrey Friedman for the kind gift of B6.Cg-Tg (Pomc-MAPT/Topaz)1Rck/J mice and Astra Zeneca for providing recombinant mouse leptin. We gratefully thank Dr. Nicola Origlia (CNR Institute of Neuroscience, Pisa) for the essential support in the execution of patch clamp experiments.
This study was funded by Telethon TDMM00707TU to MM, Italian Ministry of Education (2015 TC3Y9B) to MM.
Compliance with Ethical Standards
Animal care protocols and procedures were approved by the Italian Ministry of Health (108/2015-PR), and all experiments were performed in accordance with relevant guidelines and regulation.
Conflict of Interest
The authors declare that they have no conflict of interest.
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