Leptin regulation of hippocampal synaptic function in health and disease

Abstract

The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.

Keywords: AMPA receptor trafficking; Alzheimer's disease; hippocampus; leptin; long-term potentiation; synaptic plasticity.

Figure 1.

Differential regulation of GluA1 and GluA2 surface expression by leptin. Histogram of pooled data illustrating the effects of leptin on the surface expression of GluA1 (open bars) and GluA2 (filled bars) on hippocampal neurons (7–11 DIC). Leptin (50 nM) evoked a significant increase in GluA1 surface immunostaining after all exposure times (30–180 min). By contrast, exposure to leptin for up to 60 min increased GluA2 surface staining, whereas a significant reduction in GluA2 surface staining was observed after treatment with leptin for between 90 and 180 min.

Figure 2.

Schematic of common signalling pathways underlying activity-dependent and leptin-dependent synaptic plasticity. During LTP, activation of NMDA receptors stimulates PI 3-kinase and subsequent inhibition of GSK3β at hippocampal CA1 synapses. Activation of this pathway promotes delivery of AMPA receptors to synapses which in turn results in a persistent increase in the efficacy of excitatory synaptic transmission (LTP). In a similar manner, following leptin binding to leptin receptors, the activity of PI 3-kinase is increased resulting in AMPA receptor exocytosis and a sustained increased in synaptic efficacy (leptin-induced LTP). Although neuronal leptin receptors are capable of inhibiting GSK3β, via PI 3-kinase, it is unclear if GSK3β plays a role in leptin-induced LTP. During LTD, stimulation of NMDA receptors activates PP1 leading to increased GSK3β activity and subsequent AMPA receptor endocytosis and LTD. Activation of the JAK2-STAT3 pathway has also recently been implicated in NMDA receptor-dependent LTD. Although the JAK2-STAT3 pathway is a key downstream target of neuronal leptin receptors, it is not known if this pathway plays a role in leptin-dependent synaptic plasticity. (Online version in colour.)