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 (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    70 Citations (Scopus)

    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) P-3 levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5) P-3 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

    Keywords

    • LONG-TERM POTENTIATION
    • PROTEIN-KINASE CK2
    • HIPPOCAMPAL-NEURONS
    • TUMOR-SUPPRESSOR
    • SYNAPTIC-TRANSMISSION
    • ACTIVATION
    • BRAIN
    • PHOSPHORYLATION
    • OBESITY
    • EXPRESSION

    Cite this

    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.
    @article{f9b04ad117a14111b20847a90ac5bf67,
    title = "Leptin Regulates AMPA Receptor Trafficking via PTEN Inhibition",
    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) P-3 levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5) P-3 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.",
    keywords = "LONG-TERM POTENTIATION, PROTEIN-KINASE CK2, HIPPOCAMPAL-NEURONS, TUMOR-SUPPRESSOR, SYNAPTIC-TRANSMISSION, ACTIVATION, BRAIN, PHOSPHORYLATION, OBESITY, EXPRESSION",
    author = "Moult, {Peter R.} and Alasdair Cross and Santos, {Sandra D.} and Ana-Luisa Carvalho and Yvonne Lindsay and Connolly, {Christopher N.} and Irving, {Andrew J.} and Leslie, {Nicholas R.} and Jenni Harvey",
    year = "2010",
    month = "3",
    day = "17",
    doi = "10.1523/JNEUROSCI.3614-09.2010",
    language = "English",
    volume = "30",
    pages = "4088--4101",
    journal = "Journal of Neuroscience",
    issn = "0270-6474",
    publisher = "Society for Neuroscience",
    number = "11",

    }

    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 (Lead / Corresponding author).

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

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Leptin Regulates AMPA Receptor Trafficking via PTEN Inhibition

    AU - Moult, Peter R.

    AU - Cross, Alasdair

    AU - Santos, Sandra D.

    AU - Carvalho, Ana-Luisa

    AU - Lindsay, Yvonne

    AU - Connolly, Christopher N.

    AU - Irving, Andrew J.

    AU - Leslie, Nicholas R.

    AU - Harvey, Jenni

    PY - 2010/3/17

    Y1 - 2010/3/17

    N2 - 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) P-3 levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5) P-3 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.

    AB - 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) P-3 levels. In addition, leptin enhanced phosphorylation of the lipid phosphatase PTEN which inhibits PTEN function and elevates PtdIns(3,4,5) P-3 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.

    KW - LONG-TERM POTENTIATION

    KW - PROTEIN-KINASE CK2

    KW - HIPPOCAMPAL-NEURONS

    KW - TUMOR-SUPPRESSOR

    KW - SYNAPTIC-TRANSMISSION

    KW - ACTIVATION

    KW - BRAIN

    KW - PHOSPHORYLATION

    KW - OBESITY

    KW - EXPRESSION

    UR - http://www.scopus.com/inward/record.url?scp=77949725839&partnerID=8YFLogxK

    U2 - 10.1523/JNEUROSCI.3614-09.2010

    DO - 10.1523/JNEUROSCI.3614-09.2010

    M3 - Article

    C2 - 20237279

    VL - 30

    SP - 4088

    EP - 4101

    JO - Journal of Neuroscience

    JF - Journal of Neuroscience

    SN - 0270-6474

    IS - 11

    ER -