title: Loss of leptin receptors on hypothalamic POMC neurons alters synaptic inhibition.
abstract: Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in pro-opiomelanocortin (POMC) neurons (POMC: Lepr(-/-) GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr(-/-) GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr(-/-) GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr(-/-) GFP mice. Moreover, POMC neurons receive greater total ionic flux per GABAergic event in the absence of leptin receptor signaling. In addition, treatment with the alpha 3 subunit-containing GABA(A) receptor modulator SB-205384 enhances GABAergic transmission only onto POMC neurons in POMC: Lepr(-/-) GFP mice. Single-cell RT-PCR analysis further supports the expression of the alpha 3 subunit of the GABA(A) receptor on POMC neurons in POMC: Lepr(-/-) GFP mice. Finally, the responses to the GABA(A) receptor agonist isoguvacine of POMC neurons are significantly smaller in POMC: Lepr(-/-) GFP than in control animals. Therefore our present work demonstrates that loss of leptin signaling in POMC neurons induces synaptic alterations at POMC synapses that may play an essential role in energy homeostasis.
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10467, USA.
authors.forename: Sung Kun
authors.initials: SK
authors.lastname: Chun
authors.forename: Young-Hawn
authors.initials: YH
authors.lastname: Jo
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D011963:Receptors, GABA-A; D054411:Receptors, Leptin; D005680:gamma-Aminobutyric Acid; D011333:Pro-Opiomelanocortin