Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression

M. Guo, Y. Lu, J. C. Garza, Y. Li, Streamson C. Chua, Jr., W. Zhang, B. Lu, X. Y. Lu

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl-D-aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression.

Original languageEnglish (US)
Article numbere83
JournalTranslational Psychiatry
Volume2
DOIs
StatePublished - 2012

Fingerprint

Leptin Receptors
Prosencephalon
Leptin
Long-Term Synaptic Depression
Depression
Neurons
Antidepressive Agents
Learned Helplessness
Anhedonia
Ideal Body Weight
Long-Term Potentiation
N-Methylaspartate
Prefrontal Cortex
N-Methyl-D-Aspartate Receptors
Adipocytes
Knockout Mice
Hippocampus
Anxiety
Hormones
Growth

Keywords

  • Behavioral depression
  • GluN2B subunit
  • Glutamatergic neurons
  • Leptin receptor
  • NMDA receptors
  • Synaptic depression

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience

Cite this

Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression. / Guo, M.; Lu, Y.; Garza, J. C.; Li, Y.; Chua, Jr., Streamson C.; Zhang, W.; Lu, B.; Lu, X. Y.

In: Translational Psychiatry, Vol. 2, e83, 2012.

Research output: Contribution to journalArticle

@article{bf54d4bb89bd4c2e8543086a2a164cae,
title = "Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression",
abstract = "The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl-D-aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression.",
keywords = "Behavioral depression, GluN2B subunit, Glutamatergic neurons, Leptin receptor, NMDA receptors, Synaptic depression",
author = "M. Guo and Y. Lu and Garza, {J. C.} and Y. Li and {Chua, Jr.}, {Streamson C.} and W. Zhang and B. Lu and Lu, {X. Y.}",
year = "2012",
doi = "10.1038/tp.2012.9",
language = "English (US)",
volume = "2",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Forebrain glutamatergic neurons mediate leptin action on depression-like behaviors and synaptic depression

AU - Guo, M.

AU - Lu, Y.

AU - Garza, J. C.

AU - Li, Y.

AU - Chua, Jr., Streamson C.

AU - Zhang, W.

AU - Lu, B.

AU - Lu, X. Y.

PY - 2012

Y1 - 2012

N2 - The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl-D-aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression.

AB - The glutamatergic system has been implicated in the pathophysiology of depression and the mechanism of action of antidepressants. Leptin, an adipocyte-derived hormone, has antidepressant-like properties. However, the functional role of leptin receptor (Lepr) signaling in glutamatergic neurons remains to be elucidated. In this study, we generated conditional knockout mice in which the long form of Lepr was ablated selectively in glutamatergic neurons located in the forebrain structures, including the hippocampus and prefrontal cortex (Lepr cKO). Lepr cKO mice exhibit normal growth and body weight. Behavioral characterization of Lepr cKO mice reveals depression-like behavioral deficits, including anhedonia, behavioral despair, enhanced learned helplessness and social withdrawal, with no evident signs of anxiety. In addition, loss of Lepr in forebrain glutamatergic neurons facilitates N-methyl-D-aspartate (NMDA)-induced hippocampal long-term synaptic depression (LTD), whereas conventional LTD or long-term potentiation (LTP) was not affected. The facilitated LTD induction requires activation of the NMDA receptor GluN2B (NR2B) subunit as it was completely blocked by a selective GluN2B antagonist. Moreover, Lepr cKO mice are highly sensitive to the antidepressant-like behavioral effects of the GluN2B antagonist but resistant to leptin. These results support important roles for Lepr signaling in glutamatergic neurons in regulating depression-related behaviors and modulating excitatory synaptic strength, suggesting a possible association between synaptic depression and behavioral manifestation of behavioral depression.

KW - Behavioral depression

KW - GluN2B subunit

KW - Glutamatergic neurons

KW - Leptin receptor

KW - NMDA receptors

KW - Synaptic depression

UR - http://www.scopus.com/inward/record.url?scp=84863229399&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863229399&partnerID=8YFLogxK

U2 - 10.1038/tp.2012.9

DO - 10.1038/tp.2012.9

M3 - Article

VL - 2

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

M1 - e83

ER -