Leptin: a potential cognitive enhancer?

It is well documented that the hormone leptin signals information regarding the status of fat stores to hypothalamic nuclei, which in turn control feeding behaviour and body weight. However, leptin and its receptor are widely expressed in many extra-hypothalamic brain regions, including hippocampus, brain stem and cerebellum. Moreover, evidence is accumulating that leptin has other neuronal functions that are unrelated to its effects on energy homeostasis. Indeed a role for leptin in neuronal development has been suggested as leptin-deficient rodents display abnormal brain development and leptin actively participates in the development of the hypothalamus. In the hippocampus, leptin is a potential cognitive enhancer as genetically obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Moreover, direct administration of leptin into the hippocampus can facilitate hippocampal LTP (long-term potentiation) in vivo and improve memory processing in mice. At the cellular level, we have also shown that leptin has the capacity to convert short-term potentiation into LTP. Here, we review the data that leptin influences hippocampal synaptic plasticity via enhancing NMDA (N-methyl-D-aspartate) receptor function. We also provide evidence that rapid trafficking of NMDA receptors to the plasma membrane may underlie the effects of leptin on excitatory synaptic strength.

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

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 Ca(2+)-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 Ca(2+) levels evoked following Mg(2+) removal in hippocampal cultures. The ability of leptin to modulate this activity requires activation of BK, but not K(ATP), 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.

Leptin enhances NMDA receptor function and modulates hippocampal synaptic plasticity.

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 Ca(2+) levels ([Ca(2+)](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 Ca(2+) influx. Impairment of this process may contribute to the cognitive deficits associated with diabetes mellitus.