Leptin inhibits epileptiform-like activity in rat hippocampal neurones via PI 3-kinase-driven activation of BK channels

L. J. Shanley, D. O'Malley, A. J. Irving, M. L. Ashford, J. Harvey

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    The obese gene product, leptin is an important circulating satiety factor that regulates energy balance via its actions in the hypothalamus. However, leptin receptors are also expressed in brain regions not directly associated with energy homeostasis, such as the hippocampus. Here, leptin inhibits hippocampal neurones via activation of large conductance Ca2+-activated K+ (BK) channels, a process that may be important in regulating neuronal excitability. We now show that leptin receptor labelling is expressed on somata, dendrites and axons, and is also concentrated at synapses in hippocampal cultures. In functional studies, leptin potently and reversibly reduces epileptiform-like activity evoked in lean, but not leptin-resistant Zucker fa/fa rats. Furthermore, leptin also depresses enhanced Ca2+ levels evoked following Mg2+ removal in hippocampal cultures. The ability of leptin to modulate this activity requires activation of BK, but not KATP, channels as the effects of leptin were mimicked by the BK channel activator NS-1619, and inhibited by the BK channel inhibitors, iberiotoxin and charybdotoxin. The signalling mechanisms underlying this process involve stimulation of phosphoinositide 3-kinase (PI 3-kinase), but not mitogen-activated protein kinase (MAPK), as two structurally unrelated inhibitors of PI 3-kinase, LY294002 and wortmannin, blocked the actions of leptin. These data indicate that leptin, via PI 3-kinase-driven activation of BK channels, elicits a novel mechanism for controlling neuronal excitability. As uncontrolled excitability in the hippocampus is one underlying cause of temporal lobe epilepsy, this novel action of leptin could provide an alternative therapeutic target in the management of epilepsy. The obese gene product leptin is an important circulating, satiety factor that regulates energy balance via activation of the hypothalamic form of the leptin receptor (Ob-Rb; Jacob et al. 1997); an action that has been attributed to inhibition of hypothalamic neurones via ATP-sensitive K+ (KATP) channel activation (Spanswick et al. 1997). However, leptin receptor immunoreactivity (Hakansson et al. 1998) and mRNA (Mercer et al. 1996) are also expressed in areas of the CNS not directly associated with energy homeostasis, suggesting that leptin has additional functions in these brain regions. Leptin itself crosses the blood-brain barrier and may be released locally in the CNS (Morash et al. 1999). The leptin receptor is a member of the class I cytokine receptor superfamily (Tartaglia et al. 1995) that signals via association with janus tyrosine kinases (JAKs). Several pathways are activated by JAKs including insulin receptor substrate (IRS) proteins (Myers & White, 1996), and phosphoinositide 3-kinase (PI 3-kinase) is one protein activated downstream of IRS-1 (Shepherd et al. 1998). Indeed, leptin signals via PI 3-kinase in insulinoma cells (Harvey et al. 2000 b), muscle cells (Berti et al. 1997) and hepatocytes (Zhao et al. 2000). The main function of PI 3-kinase is to convert phosphatidylinositol bisphosphate (PtdIns(4,5)P2) into phosphatidylinositol trisphosphate (PtdIns(3,4,5)P3; Shepherd et al. 1998). Signalling cascades activated downstream of PI 3-kinase that utilise PtdIns(3,4,5)P3 as a second messenger include mitogen-activated protein kinase (MAPK), stress-activated protein kinase 2 (SAPK2) and protein kinase B. Indeed, activation of MAPK has also been implicated as a signalling intermediate for leptin (Takahashi et al. 1997; Tanabe et al. 1997). Hippocampal neurones also express high levels of IRS-1, PI 3-kinase (Folli et al. 1994) and MAPK (Fiore et al. 1993). Indeed, leptin modulates NMDA receptor function in the hippocampus via a PI 3-kinase- and MAPK-dependent process (Shanley et al. 2001). We have shown recently that leptin inhibits hippocampal neurones via activation of large conductance Ca2+-activated K+ (BK) channels (Shanley et al. 2002). Neuronal BK channel activity is highly dependent on the levels of intracellular Ca2+ ([Ca2+]i) at any given voltage (Latorre, 1989). BK channels are activated during an action potential when the membrane potential depolarises and [Ca2+]i rises, and are critical in determining action potential firing rates as well as burst firing patterns. As leptin activates BK channels in hippocampal neurones (Shanley et al. 2002), we hypothesised that leptin, via BK channel stimulation, could modulate aberrant synaptic activity in hippocampal neurones. In this study we show, using hippocampal slices and cultured neurones, that leptin inhibits epileptiform-like activity via PI 3-kinase-driven BK channel activation. This process represents a novel mechanism for controlling hippocampal excitability. Some of these data have been published previously in abstract form (Shanley et al. 2000).

    Original languageEnglish
    Pages (from-to)933-944
    Number of pages12
    JournalJournal of Physiology
    Issue number3
    Publication statusPublished - Dec 2002


    • Epilepsy physiopathology
    • Hippocampus physiopathology
    • Leptin physiology
    • Neurons physiology
    • Phosphatidylinositol 3-kinases physiology
    • Potassium channels
    • Calcium-activated physiology


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