Leptin induces a novel form of NMDA receptor-dependent long-term depression
Article first published online: 8 AUG 2005
Journal of Neurochemistry
Volume 95, Issue 2, pages 396–405, October 2005
How to Cite
Durakoglugil, M., Irving, A. J. and Harvey, J. (2005), Leptin induces a novel form of NMDA receptor-dependent long-term depression. Journal of Neurochemistry, 95: 396–405. doi: 10.1111/j.1471-4159.2005.03375.x
- Issue published online: 12 SEP 2005
- Article first published online: 8 AUG 2005
- Received April 5, 2005; revised manuscript received June 17, 2005; Accepted June 20, 2005.
- long-term depression;
- NMDA receptor-dependent
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 GABAA 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.