Elsevier

Biological Psychiatry

Volume 73, Issue 9, 1 May 2013, Pages 860-868
Biological Psychiatry

Archival Report
Presynaptic Leptin Action Suppresses Excitatory Synaptic Transmission onto Ventral Tegmental Area Dopamine Neurons

https://doi.org/10.1016/j.biopsych.2012.10.026Get rights and content

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Section snippets

Animals

All protocols were in accordance with the ethical guidelines established by the Canadian Council for Animal care and were approved by the University of British Columbia Animal Care Committee. Male C57BL/6 mice (p21–25; University of British Columbia) were housed in groups of 3 to 5. For some experiments, mice expressing pituitary homeobox 3 tagged with green fluorescent protein (Pitx3-GFP) knock-in mice (p21–25; bred inhouse) were used to easily identify VTA dopaminergic neurons because Pitx3

Leptin Suppresses Excitatory Synaptic Transmission onto VTA Dopamine Neurons

AMPAR EPSCs were recorded from VTA dopamine neurons of mouse midbrain slices voltage-clamped at –70 mV. Bath application of leptin for 15 min caused a long-lasting depression of AMPAR EPSCs (Figure 1A,B; baseline: 98%±1% vs. leptin: 77%±6%; n = 7, p<.05). Leptin depressed AMPAR EPSCs in all four neurons that were post hoc labeled for TH. To measure NMDAR EPSCs, neurons were voltage clamped at +40 mV and measurements were taken 20 ms after the stimulus artifact, a time point at which the

Discussion

The data presented here establish a novel mechanism for leptin action in the mesolimbic incentive motivation/reward system. Leptin reduced both NMDAR- and AMPAR-mediated synaptic transmission onto dopamine neurons by reducing glutamate release from presynaptic terminals. This effect was mediated by presynaptic Jak2 and PI3K signaling, suggesting that leptin is not directly activating dopamine neurons to induce synaptic inhibition. A model of leptin inhibition of excitatory synaptic transmission

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