In addition to facilitating hippocampal LTP, a recent study has demonstrated that the hormone leptin has the ability to induce a novel form of LTD in the CA1 region of the hippocampus [72
]. It is well documented that long-term depression (LTD) of excitatory synaptic transmission is a persistent weakening of synaptic strength that is involved in learning and memory processes and neuronal development. Two main forms are known to exist in the mammalian CNS that are induced by the synaptic activation of NMDA [80
] and metabotropic glutamate receptors [81
], respectively. In contrast to these established forms of NMDA receptor-dependent LTD, the LTD induced by leptin was only apparent under conditions of enhanced excitability evoked by either Mg2+
-free medium or following blockade of GABAA
receptors with picrotoxin. Moreover leptin failed to induce any long lasting change in synaptic strength under basal conditions [72
]. However, in a manner similar to the LTD induced by either low frequency stimulation (LFS) or mGluR activation, leptin-induced LTD was dependent on the synaptic activation of NMDA receptors as it was markedly attenuated by the competitive NMDA receptor antagonist, D-AP5. In contrast, mGluRs were not involved in the induction of leptin-induced LTD as prior incubation of hippocampal slices with a combination of group 1a (LY367385) and group 5 (MPEP) mGluR antagonists did not affect the ability of leptin to induce LTD. Similarly mGluRs were not involved in the maintenance phase of leptin-induced LTD as blockade of either group II mGluRs (LY341495) or group 1a/5 mGluRs (MPEP plus LY367385) failed reverse the LTD induced by leptin. In occlusion studies, Durakoglugil et al [72
] also demonstrated that leptin-induced LTD and LFS-induced LTD share at least some similar expression mechanisms. Thus, following saturation of LFS-induced LTD, leptin failed to reduce synaptic responses further, whereas following induction of LTD by leptin, subsequent LFS still depressed synaptic transmission.
Interestingly the hormone insulin, which displays many parallels to leptin in terms of its downstream signaling capability and its cellular targets in neurons, can also induce a form of NMDA receptor-dependent hippocampal LTD [83
]. In a manner analogous to leptin, the LTD induced by insulin was only apparent when neuronal excitability was increased by either blockade of GABAA
receptor-mediated fast inhibitory synaptic transmission, or by lowering the extracellular levels of Mg2+
Previous immunocytochemical studies have shown that leptin receptors are expressed at both pre- and post-synaptic sites at hippocampal CA1 synapses [30
]. Thus, leptin-induced LTD could conceivably be expressed at either locus. In order to determine the locus of this form of LTD, Durakoglugil et al [72
] examined the effects of leptin on the degree of paired-pulse facilitation (PPF) induced when two stimuli were delivered with an inter-stimulus interval of 50 ms. The effects of leptin were compared to adenosine, as adenosine depresses excitatory synaptic transmission at this synapse by a presynaptic mechanism [85
]. Under conditions where leptin depressed synaptic transmission, there was no significant corresponding change in the PPF ratio, whereas the depression evoked by adenosine was paralleled by a marked change in the PPF ratio. Thus leptin-induced LTD is most likely to be expressed postsynaptically.
8. 1. Leptin-induced LTD is negatively regulated by PI 3-kinase and serine/threonine phosphatases.
Durakoglugil et al [72
] also examined the signaling pathways underlying leptin-induced LTD. In contrast to the ability of leptin to promote hippocampal LTP, a MAPK-independent process underlies leptin-induced LTD. Thus, incubation of hippocampal slices with either PD98059 or U0126 to inhibit MAPK activation, did not affect the ability of leptin to induce LTD. Moreover, inhibition of PI 3-kinase with either wortmannin or LY294002 did not attenuate, but rather markedly enhanced the level of LTD induced by leptin [72
], suggesting that leptin-induced LTD is negatively regulated by PI 3-kinase. Interestingly this is also in contrast to insulin-induced LTD which is attenuated by PI 3-kinase inhibitors [83
Serine/threonine phosphatases are also implicated in the regulation of leptin-induced LTD as okadaic acid, a protein phosphatase 1/2A (PP1/2A) inhibitor, significantly enhanced the degree of LTD induced by leptin. In contrast, inhibitors of protein phosphatase 2B (cypermethrin or cyclosporine) had no effect on the ability of leptin to induce LTD ().