Bi-directional modulation of fast inhibitory synaptic transmission by leptin.
The hormone leptin has widespread actions in the CNS. Indeed, leptin markedly influences hippocampal excitatory synaptic transmission and synaptic plasticity. However, the effects of leptin on fast inhibitory synaptic transmission in the hippocampus have not been evaluated. Here, we show that leptin modulates GABA(A) receptor-mediated synaptic transmission onto hippocampal CA1 pyramidal cells. Leptin promotes a rapid and reversible increase in the amplitude of evoked GABA(A) receptor-mediated inhibitory synaptic currents (IPSCs); an effect that was paralleled by increases in the frequency and amplitude of miniature IPSCs, but with no change in paired pulse ratio or coefficient of variation, suggesting a post-synaptic expression mechanism. Following washout of leptin, a persistent depression (inhibitory long-lasting depression) of evoked IPSCs was observed. Whole-cell dialysis or bath application of inhibitors of phosphoinositide 3 (PI 3)-kinase or Akt prevented leptin-induced enhancement of IPSCs indicating involvement of a post-synaptic PI 3-kinase/Akt-dependent pathway. In contrast, blockade of PI 3-kinase or Akt activity failed to alter the ability of leptin to induce inhibitory long-lasting depression, suggesting that this process is independent of PI 3-kinase/Akt. In conclusion these data indicate that the hormone leptin bi-directionally modulates GABA(A) receptor-mediated synaptic transmission in the hippocampus. These findings have important implications for the role of this hormone in regulating hippocampal pyramidal neuron excitability.
Solovyova
Natasha
N
Neurosciences Institute, Division of Pathology & Neuroscience, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK.
Moult
Peter R
PR
Milojkovic
Bogdan
B
Lambert
Jeremy J
JJ
Harvey
Jenni
J
D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D018755:GABA Agonists; D018756:GABA Antagonists; D020738:Leptin; D009118:Muscimol; D010852:Picrotoxin