Leptin and its role in hippocampal synaptic plasticity

Abstract

It is well documented that the hormone leptin plays a pivotal role in regulating food intake and body weight via its hypothalamic actions. However, leptin receptors are expressed throughout the brain with high levels found in the hippocampus. Evidence is accumulating that leptin has widespread actions on CNS function and in particular learning and memory. Recent studies have demonstrated that leptin-deficient or-insensitive rodents have impairments in hippocampal synaptic plasticity and in spatial memory tasks performed in the Morris water maze. Moreover, direct administration of leptin into the brain facilitates hippocampal long-term potentiation (LTP), and improves memory performance in mice. There is also evidence that, at the cellular level, leptin has the capacity to convert hippocampal short-term potentiation (STP) into LTP, via enhancing NMDA receptor function. Recent data indicates that leptin can also induce a novel form of NMDA receptor-dependent hippocampal long-term depression. Here, we review the evidence implicating a key role for the hormone leptin in modulating hippocampal synaptic plasticity and discuss the role of lipid signaling cascades in this process.

Figure 1

Signalling pathways activated by leptin. In a manner similar to other cytokines, activation of the long form of the leptin receptor promotes the stimulation of a number of signaling molecules including STAT3, MAPK and PI 3-kinase.

Figure 2

Leptin influences NMDA receptor-dependent hippocampal synaptic plasticity. Schematic representation of the possible mechanisms underlying the effects of leptin on hippocampal synaptic plasticity. Leptin promotes the conversion of STP into LTP via selective enhancement of NMDA receptor function. This process involves the activation of MAPK, PI 3-kinase and Src tyrosine kinases. In contrast, under conditions of enhanced excitability leptin evokes a novel form of NMDA receptor-dependent LTD that is independent of MAPK activation but is negatively regulated by PI 3-kinase and calcineurin (PP2B).