Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity

Lynne J. Shanley, Andrew J. Irving, Jenni Harvey

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    311 Citations (Scopus)


    The obese gene product leptin is an important signaling protein that regulates food intake and body weight via activation of the hypothalamic leptin receptor (Ob-Rb; Jacob et al., 1997). However, there is growing evidence that Ob-Rb is also expressed in CNS regions, not directly associated with energy homeostasis (Mercer et al., 1996; Hakansson et al., 1998). In the hippocampus, an area of the brain involved in learning and memory, we have found that leptin facilitates the induction of synaptic plasticity. Leptin converts short-term potentiation of synaptic transmission induced by primed burst stimulation of the Schaffer collateral commissural pathway into long-term potentiation. The mechanism underlying this effect involves facilitation of NMDA receptor function because leptin rapidly enhances NMDA-induced increases in intracellular Ca2 levels ([Ca2 ]i ) and facilitates NMDA, but not AMPA, receptor-mediated synaptic transmission. The signaling mechanism underlying these effects involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinase, and Src tyrosine kinases. These data indicate that a novel action of leptin in the CNS is to facilitate hippocampal synaptic plasticity via enhanced NMDA receptor-mediated Ca2 influx. Impairment of this process may contribute to the cognitive deficits associated with diabetes mellitus.
    Original languageEnglish
    Pages (from-to)RC186-1-RC186-6
    JournalJournal of Neuroscience
    Issue number24
    Publication statusPublished - Dec 2001


    • Leptin
    • Ca2+ imaging
    • PI 3-kinase
    • MAPK
    • Src tyrosine kinase
    • Neuronal plasticity physiology
    • Receptors
    • N-Methyl-D-Aspartate metabolism
    • NMDA
    • Synaptic transmission physiology


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