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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Animals, Butadienes, Dopaminergic Neurons, Enzyme Inhibitors, Excitatory Postsynaptic Potentials, Leptin, Male, Mice, Nitriles, Patch-Clamp Techniques, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Signal Transduction, Synaptic Transmission, Ventral Tegmental Area.
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Does presynaptic leptin action suppress excitatory synaptic transmission onto ventral tegmental area dopamine neurons? Context: Leptin is an adipocyte-derived cytokine that can act in the brain to suppress feeding and maintain energy homeostasis. Additionally, leptin activates its receptors in the ventral tegmental area (VTA), a critical site for neuroadaptations to rewarding stimuli, to modulate reward-seeking behaviors. Although leptin can decrease intrinsic excitability of dopamine neurons in the VTA, it is unknown whether leptin can modulate excitatory synaptic transmission in this brain region. Because plasticity of glutamatergic synapses onto VTA neurons can encode predictive information about reward, we hypothesized that leptin can decrease excitatory synaptic transmission onto dopamine neurons. Using whole-cell patch clamp electrophysiology in mouse midbrain slices, we tested the effects of leptin on evoked α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) or N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory postsynaptic currents (EPSCs) onto VTA dopamine neurons. Leptin depressed both AMPAR and NMDAR EPSCs in VTA dopamine neurons and reduced frequency but not amplitude of mini EPSCs. Bath application of the MEK1/2 inhibitor U0126 did not alter leptin-induced suppression of AMPAR EPSCs. However, external, but not internal, application of the phosphoinositol 3-kinase (PI3K) or Janus kinase 2 (Jak2) tyrosine kinase inhibitors abolished leptin-induced synaptic depression.
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This study demonstrates that leptin causes a presynaptic inhibition of the probability of glutamate release onto VTA dopamine neurons. This synaptic inhibition requires Jak2 and PI3K activation. Leptin-induced weakening of synaptic strength onto dopamine cells may underlie its inhibitory effects on appetitive behavior for rewarding stimuli. Final Decision: yes