Leptin and the CNS
It is well established that the endocrine hormone leptin circulates in the plasma and enters the brain where it plays a pivotal role in the hypothalamic regulation of energy homeostasis. However, evidence is accumulating that leptin receptors are widely expressed in the CNS and that leptin is capable of modulating numerous brain functions. In the hippocampus in particular, leptin has been shown to be an important modulator of associative learning and memory processes. Indeed, leptin-insensitive rodents display impaired hippocampal synaptic plasticity as well as defects in spatial memory tasks. Moreover, at the cellular level, leptin facilitates NMDA receptor–dependent LTP, evokes a novel form of de novo LTD, reverses LTP (depotentiation), and evokes rapid dendritic morphogenesis. There is also evidence that leptin is a potent regulator of neuronal excitability. Indeed, in the hippocampal formation, leptin can regulate pyramidal neuron excitability via either direct activation of BK channels or indirectly via modulation of the inhibitory tone onto pyramidal neurons. Leptin also regulates the excitability of other types of neurons including hypothalamic and dorsal motor nucleus neurons, via activation of potassium channels. More recent studies indicate that disturbances in the leptin system may play a role not only in healthy aging but also in the development of neurodegenerative diseases associated with cognitive deficits such as Alzheimer’s disease. Indeed, reductions in the circulating levels of leptin are common features in patients with Alzheimer’s disease. Recently, leptin has also been implicated in neuropsychological disorders as leptin has antidepressant properties and human cases of major depression have been linked to attenuated circulating leptin levels. In this chapter, we review the recent advances in leptin neurobiology. In particular, the key role of leptin in controlling extra-hypothalamic brain functions is discussed.
KeywordsNMDA Receptor AMPA Receptor Excitatory Synaptic Transmission Hippocampal Synaptic Plasticity Competitive NMDA Receptor Antagonist
Large conductance Ca2+-activated K+ channel.
Central nervous system
Extracellular signal regulated kinase
Excitatory postsynaptic current
Inhibitory postsynaptic current.
Insulin receptor substrate
Janus tyrosine kinase
ATP-sensitive K+ channel
Mitogen-activated protein kinase.
- PI 3-kinase
Protein kinase C
Signal transducer and activator of transcription
JH is funded by grants from The Cunningham Trust, The Wellcome Trust and The Anonymous Trust.
- Hervey GR. J Physiol. 1958;145:336–52.Google Scholar