Leptin reverses long-term potentiation at hippocampal CA1 synapses

• Published in: Journal of neurochemistry 2009-02, Vol.108 (3), p.685-696
• Main Authors: Moult, Peter R, Milojkovic, Bogdan, Harvey, Jenni
• Format: Article
• Language: English
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Animals; Antagonist drugs; Biochemistry; Biological and medical sciences; calcineurin; Calcineurin - physiology; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; depotentiation; Electric Stimulation; Electrophysiology; Enzyme Activation - drug effects; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Postsynaptic Potentials - drug effects; Fundamental and applied biological sciences. Psychology; hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Humans; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases - metabolism; leptin; Leptin - pharmacology; Long-Term Potentiation - drug effects; Male; Neurology; Neurons; Neurotransmitters; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, AMPA - drug effects; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - drug effects; Synapses - drug effects; Synapses - metabolism; synaptic plasticity; Vertebrates: nervous system and sense organs; α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05810.x

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 NH₂ terminal kinase. Furthermore, leptin-induced depotentiation was accompanied by a reduction in α-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.