title: Leptin reverses long-term potentiation at hippocampal CA1 synapses.
abstract: The hormone leptin crosses the blood brain barrier and regulates numerous neuronal functions, including hippocampal synaptic plasticity. Here we show that application of leptin resulted in the reversal of long-term potentiation (LTP) at hippocampal CA1 synapses. The ability of leptin to depotentiate CA1 synapses was concentration-dependent and it displayed a distinct temporal profile. Leptin-induced depotentiation was not associated with any change in the paired pulse facilitation ratio or the coefficient of variance, indicating a post-synaptic locus of expression. Moreover, the synaptic activation of NMDA receptors was required for leptin-induced depotentiation as the effects of leptin were blocked by the competitive NMDA receptor antagonist, D-aminophosphovaleric acid (D-AP5). The signaling mechanisms underlying leptin-induced depotentiation involved activation of the calcium/calmodulin-dependent protein phosphatase, calcineurin, but were independent of c-jun NH(2) terminal kinase. Furthermore, leptin-induced depotentiation was accompanied by a reduction in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor rectification indicating that loss of glutamate receptor 2 (GluR2)-lacking AMPA receptors underlies this process. These data indicate that leptin reverses hippocampal LTP via a process involving calcineurin-dependent internalization of GluR2-lacking AMPA receptors which further highlights the key role for this hormone in regulating hippocampal synaptic plasticity and neuronal development.
authors.affiliation: Neurosciences Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Moult
authors.forename: Bogdan
authors.initials: B
authors.lastname: Milojkovic
authors.forename: Jenni
authors.initials: J
authors.lastname: Harvey
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000502:physiology; D004558:Electric Stimulation; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D020738:Leptin; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D015763:2-Amino-5-phosphonovalerate; D048031:JNK Mitogen-Activated Protein Kinases; D019703:Calcineurin; C104722:glutamate receptor ionotropic, AMPA 2