Leptin induces a novel form of NMDA receptor-dependent long-term depression.
It is becoming apparent that the hormone leptin plays an important role in modulating hippocampal function. Indeed, leptin enhances NMDA receptor activation and promotes hippocampal long-term potentiation (LTP). Furthermore, obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Here we demonstrate that under conditions of enhanced excitability (evoked in Mg2+-free medium or following blockade of GABA(A) receptors), leptin induces a novel form of long-term depression (LTD) in area CA1 of the hippocampus. Leptin-induced LTD was markedly attenuated in the presence of D-(-)-2-Amino-5-Phosphonopentanoic acid (D-AP5), suggesting that it is dependent on the synaptic activation of NMDA receptors. In addition, low-frequency stimulus-evoked LTD occluded the effects of leptin. In contrast, metabotropic glutamate receptors (mGluRs) did not contribute to leptin-induced LTD as mGluR antagonists failed to either prevent or reverse this process. The signalling mechanisms underlying leptin-induced LTD were independent of the Ras-Raf-mitogen-activated protein kinase signalling pathway, but were markedly enhanced following inhibition of either phosphoinositide 3-kinase or protein phosphatases 1 and 2A. These data indicate that under conditions of enhanced excitability, leptin induces a novel form of homosynaptic LTD, which further underscores the proposed key role for this hormone in modulating NMDA receptor-dependent hippocampal synaptic plasticity.
Durakoglugil
Murat
M
Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee UK.
Irving
Andrew J
AJ
Harvey
Jenni
J
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D003864:Depression, Chemical; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects
D015763:2-Amino-5-phosphonovalerate; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D020738:Leptin; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate