NMDA receptor subunit composition determines the polarity of leptin-induced synaptic plasticity
Highlights
► We have studied leptin regulation of hippocampal excitatory synaptic transmission. ► Early in development leptin induces LTD of synaptic transmission. ► In adult leptin evokes a persistent increase in hippocampal synaptic efficacy. ► Distinct NMDA receptor subunits mediate the age-dependent effects of leptin. ► The age-dependent effects of leptin involve divergent signalling pathways.
Introduction
Synaptic plasticity is one of the most widely studied phenomena of the mammalian central nervous system (CNS). There is compelling evidence that activity-dependent forms of synaptic plasticity such as hippocampal long-term potentiation (LTP) and long-term depression (LTD) are cellular correlates for information storage within the CNS (Bliss and Collingridge, 1993). However, recent studies have focused on the modulation of synaptic strength by various endogenous hormonal systems, such as insulin (Huang et al., 2004, Man et al., 2000, Man et al., 2003, van der Heide et al., 2005), estrogens (McEwen, 2002) and leptin (Harvey et al., 2006). Leptin is a 167 kDa protein that circulates in the plasma at concentrations relative to body fat. Extensive research has identified a role for leptin in regulating satiety and energy homeostasis via its hypothalamic actions (Spiegelman and Flier, 2001). However the effects of leptin are not restricted to the hypothalamus. Indeed, recent evidence indicates that leptin plays an important role in modulating many neuronal functions including hippocampal synaptic plasticity and glutamate receptor trafficking (Durakoglugil et al., 2005, Irving et al., 2006, Moult et al., 2010, Moult et al., 2009, Shanley et al., 2001). Moreover, it has been shown that leptin-insensitive rodents display impaired hippocampal LTP, LTD and spatial memory (Li et al., 2002), and administration of leptin into rodent hippocampus improves memory processing (Wayner et al., 2004). In addition, leptin has the ability to facilitate hippocampal LTP (Shanley et al., 2001) and promote the induction of a novel form of de novo hippocampal LTD (Durakoglugil et al., 2005). Recent evidence indicates that leptin promotes an increase in the synaptic expression of GluA2-lacking AMPA receptors in adult hippocampal slices resulting in a persistent increase in the efficacy of excitatory synaptic transmission (Moult et al., 2010). In contrast to its effects in adult, leptin evokes a transient depression of excitatory synaptic transmission in juvenile hippocampus (Shanley et al., 2001, Xu et al., 2008), suggesting that leptin modulates excitatory synaptic transmission in an age-dependent manner. In order to determine the cellular basis for this age-dependence, we have systematically examined the effects of leptin on excitatory synaptic transmission in hippocampal slices at four distinct ages. Here we show that the direction of synaptic modulation by leptin is age-dependent such that at early stages of postnatal development leptin results in either a transient (P11–18) or persistent (P5–8) depression of synaptic transmission, whereas in adult hippocampus (12–16 week and 12–14 month) leptin evokes a long lasting increase in excitatory synaptic strength. Although there are distinct age-dependent differences in the polarity and duration of synaptic modulation induced by leptin, the effects of leptin required NMDA receptor activation at all ages examined. Moreover, the ability of leptin to alter excitatory synaptic transmission displayed subunit-specific NMDA receptor dependence such that at early stages of postnatal development the effects of leptin required the activation of GluN2B NMDA subunits, whereas in adult hippocampus the leptin-driven persistent increase in synaptic strength was mediated by GluN2A subunits. In addition, divergent signalling pathways were found to mediate the effects of leptin at different ages. Thus, both the long lasting (P5–8) and transient (P11–18) synaptic depressions induced by leptin involved the activation of the ERK signalling cascade, whereas the leptin-driven persistent increase in synaptic strength in adult was mediated by a PI 3-kinase-dependent mechanism. Moreover, occlusion studies show that synaptically induced LTP occludes the persistent synaptic potentiation induced by leptin in adult hippocampus and vice versa, suggesting that HFS-induced LTP and leptin-induced LTP share similar expression mechanisms. Similarly, synaptically induced LTD occludes the persistent depression induced by leptin early in development (P5–8) and vice versa, indicating that analogous expression mechanisms also underlie leptin-induced LTD and LFS-induced LTD. These findings have important implications for the role of leptin in regulating hippocampal synaptic strength.
Section snippets
Materials and methods
Hippocampal slices (350 μm) were prepared from P5–8, P11–18, 12–16 week or 12–14 month old, male Sprague–Dawley rats. Animals were killed by cervical dislocation (P5–8, P11–18 and 12–16 week) or deep anaesthesia with isofluorane followed by decapitation (12–14 month) according to UK (Scientific Procedures Act 1986) legislation. Brains were rapidly removed and placed in ice-cold artificial cerebrospinal fluid (aCSF; bubbled with 95% O2 and 5% CO2) containing (in mM): 124 NaCl, 3 KCl, 26 NaHCO3,
Leptin modulates excitatory synaptic transmission in an age-dependent manner
We have recently shown that leptin results in a persistent increase in excitatory synaptic transmission in adult hippocampal slices (12–16 week old; Moult et al., 2010). In contrast, we and others have demonstrated that leptin transiently depresses excitatory synaptic transmission in juvenile hippocampus (Shanley et al., 2001, Xu et al., 2008). In order to determine the cellular basis for the bi-directional modulation of synaptic transmission by leptin, we examined the effects of leptin (25 nM)
Discussion
It is well established that leptin regulates a number of hypothalamic-driven functions including energy balance, reproduction and the control of bone formation (Caprio et al., 2001, Spiegelman and Flier, 2001, Takeda and Karsenty, 2001). However, evidence is accumulating that leptin is a multi-faceted hormone with widespread actions in the CNS. Indeed, leptin receptors are highly expressed in the hippocampal formation (Mercer et al., 1996, Shanley et al., 2002) and several lines of evidence
Acknowledgements
This work was supported by the Wellcome Trust (075821) and Medical Research Scotland.
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