Leptin reverses long-term potentiation at hippocampal CA1 synapses.
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.
Moult
Peter R
PR
Neurosciences Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
Milojkovic
Bogdan
B
Harvey
Jenni
J
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
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