Leptin regulates AMPA receptor trafficking via PTEN inhibition

Peter R. Moult, Alasdair Cross, Sandra D. Santos, Ana-Luisa Carvalho, Yvonne Lindsay, Christopher N. Connolly, Andrew J. Irving, Nicholas R. Leslie, Jenni Harvey

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Abstract

The hormone leptin can cross the blood–brain barrier and influences numerous brain functions (Harvey, 2007). Indeed, recent studies have demonstrated that leptin regulates activity-dependent synaptic plasticity in the CA1 region of the hippocampus (Shanley et al., 2001; Li et al., 2002; Durakoglugil et al., 2005; Moult et al., 2009). It is well documented that trafficking of AMPA receptors is pivotal for hippocampal synaptic plasticity (Collingridge et al., 2004), but there is limited knowledge of how hormonal systems like leptin influence this process. In this study we have examined how leptin influences AMPA receptor trafficking and in turn how this impacts on excitatory synaptic function. Here we show that leptin preferentially increases the cell surface expression of GluR1 and the synaptic density of GluR2-lacking AMPA receptors in adult hippocampal slices. The leptin-induced increase in surface GluR1 required NMDA receptor activation and was associated with an increase in cytoplasmic PtdIns(3,4,5)P3 levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5)P3 levels. Moreover, inhibition of PTEN mimicked and occluded the effects of leptin on GluR1 trafficking and excitatory synaptic strength. These data indicate that leptin, via a novel pathway involving PTEN inhibition, promotes GluR1 trafficking to hippocampal synapses. This process has important implications for the role of leptin in hippocampal synaptic function in health and disease.
Original languageEnglish
Pages (from-to)4088-4101
Number of pages14
JournalJournal of Neuroscience
Volume30
Issue number11
DOIs
Publication statusPublished - 17 Mar 2010

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AMPA Receptors
Leptin
Neuronal Plasticity
PTEN Phosphohydrolase
N-Methyl-D-Aspartate Receptors
Synapses
Hippocampus
Phosphorylation
Hormones
Lipids

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Moult, P. R., Cross, A., Santos, S. D., Carvalho, A-L., Lindsay, Y., Connolly, C. N., ... Harvey, J. (2010). Leptin regulates AMPA receptor trafficking via PTEN inhibition. Journal of Neuroscience, 30(11), 4088-4101. https://doi.org/10.1523/JNEUROSCI.3614-09.2010
Moult, Peter R. ; Cross, Alasdair ; Santos, Sandra D. ; Carvalho, Ana-Luisa ; Lindsay, Yvonne ; Connolly, Christopher N. ; Irving, Andrew J. ; Leslie, Nicholas R. ; Harvey, Jenni. / Leptin regulates AMPA receptor trafficking via PTEN inhibition. In: Journal of Neuroscience. 2010 ; Vol. 30, No. 11. pp. 4088-4101.
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Moult, PR, Cross, A, Santos, SD, Carvalho, A-L, Lindsay, Y, Connolly, CN, Irving, AJ, Leslie, NR & Harvey, J 2010, 'Leptin regulates AMPA receptor trafficking via PTEN inhibition', Journal of Neuroscience, vol. 30, no. 11, pp. 4088-4101. https://doi.org/10.1523/JNEUROSCI.3614-09.2010

Leptin regulates AMPA receptor trafficking via PTEN inhibition. / Moult, Peter R.; Cross, Alasdair; Santos, Sandra D.; Carvalho, Ana-Luisa; Lindsay, Yvonne; Connolly, Christopher N.; Irving, Andrew J.; Leslie, Nicholas R.; Harvey, Jenni.

In: Journal of Neuroscience, Vol. 30, No. 11, 17.03.2010, p. 4088-4101.

Research output: Contribution to journalArticle

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Moult PR, Cross A, Santos SD, Carvalho A-L, Lindsay Y, Connolly CN et al. Leptin regulates AMPA receptor trafficking via PTEN inhibition. Journal of Neuroscience. 2010 Mar 17;30(11):4088-4101. https://doi.org/10.1523/JNEUROSCI.3614-09.2010