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Presynaptic leptin action suppresses excitatory synaptic transmission onto ventral tegmental area dopamine neurons.
Biol Psychiatry 2013; 73(9):860-8BP

Abstract

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.

Authors+Show Affiliations

Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23305991

Citation

Thompson, Jennifer L., and Stephanie L. Borgland. "Presynaptic Leptin Action Suppresses Excitatory Synaptic Transmission Onto Ventral Tegmental Area Dopamine Neurons." Biological Psychiatry, vol. 73, no. 9, 2013, pp. 860-8.
Thompson JL, Borgland SL. Presynaptic leptin action suppresses excitatory synaptic transmission onto ventral tegmental area dopamine neurons. Biol Psychiatry. 2013;73(9):860-8.
Thompson, J. L., & Borgland, S. L. (2013). Presynaptic leptin action suppresses excitatory synaptic transmission onto ventral tegmental area dopamine neurons. Biological Psychiatry, 73(9), pp. 860-8. doi:10.1016/j.biopsych.2012.10.026.
Thompson JL, Borgland SL. Presynaptic Leptin Action Suppresses Excitatory Synaptic Transmission Onto Ventral Tegmental Area Dopamine Neurons. Biol Psychiatry. 2013 May 1;73(9):860-8. PubMed PMID: 23305991.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Presynaptic leptin action suppresses excitatory synaptic transmission onto ventral tegmental area dopamine neurons. AU - Thompson,Jennifer L, AU - Borgland,Stephanie L, Y1 - 2013/01/07/ PY - 2012/07/14/received PY - 2012/10/31/revised PY - 2012/10/31/accepted PY - 2013/1/12/entrez PY - 2013/1/12/pubmed PY - 2013/10/22/medline SP - 860 EP - 8 JF - Biological psychiatry JO - Biol. Psychiatry VL - 73 IS - 9 N2 - 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. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/23305991/Presynaptic_leptin_action_suppresses_excitatory_synaptic_transmission_onto_ventral_tegmental_area_dopamine_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(12)00953-5 DB - PRIME DP - Unbound Medicine ER -