Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease

Abstract

Discovery of the obese (ob) gene in 1994 via positional cloning techniques enabled insight into the physiological system that controls body weight and energy expenditure [1]. Subsequent investigations identified the ob gene product as a 16 kDa protein that reduced food intake and increased energy expenditure in genetically obese (ob/ob) rodent models, indicating a pivotal role in regulating energy homeostasis. This protein was termed leptin [2,3].Leptin is primarily produced and secreted by white adipose tissue and circulates in proportion to adipose mass [3]. The leptin receptor (Ob-R) is encoded by the diabetes (db) gene [4]. Leptin gains access to the hypothalamus to regulate energy homeostasis via a saturable transport mechanism or by binding to receptors at the blood-brain barrier interface [5]. However recent evidence suggests that leptin can also be made locally within the CNS as leptin mRNA and protein has been detected within the brain [6].At least six different isoforms (Ob-R a-f ) of Ob-R exist (Fig. 1) as a result of alternative splicing of the db gene [7,8]. Each isoform has an identical N-terminal ligand-binding domain but a differential C-terminal region required for signalling. Each isoform gives rise to a single membranespanning receptor with the exception of Ob-R e which is thought to circulate as a soluble leptin binding protein. The remaining Ob-R isoforms have either a short intracellular domain containing 30-40 cytoplasmic residues (Ob-R a,c,d,f ) or a large intracellular domain consisting of 302 residues (known as the long form of the receptor (Ob-R b ), which is the most signalling competent form of the receptor [9].Abstract Growing evidence indicates that the endocrine hormone leptin regulates hippocampal synaptic function in addition to its established role as a hypothalamic satiety signal. Indeed, numerous studies show that leptin facilitates the cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and glutamate receptor trafficking, indicating that leptin may be a potential cognitive enhancer. Although there has been extensive investigation into the modulatory role of leptin at hippocampal Schaffer collateral (SC)-CA1 synapses, recent evidence indicates that leptin also potently regulates excitatory synaptic transmission at the anatomically distinct temporoammonic (TA) input to hippocampal CA1 neurons. The cellular mechanisms underlying activity-dependent synaptic plasticity at TA-CA1 synapses differ from those at SC-CA1 synapses and the TA input is implicated in spatial and episodic memory formation. Furthermore, the TA input is an early target for neurodegeneration in Alzheimer's disease (AD) and aberrant leptin function is linked to AD. Here, we review the evidence that leptin regulates hippocampal synaptic function at both SC-and TA-CA1 synapses and discuss the consequences for neurodegenerative disorders like AD.

Leptin modulates olfactory discrimination and neural activity in the olfactory bulb

“…40,58 Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. 61,62 In contrast to these mechanisms, we found that the voltage-sensitive potassium channel is the target of leptin in OB neurons. 60 In the hippocampus, leptin rapidly enhances NMDAinduced increases in intracellular Ca 2+ levels and facilitates NMDA currents, but not AMPA currents; the underlying signaling mechanism involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinase, and Src tyrosine kinases.…”

“…60 In the hippocampus, leptin rapidly enhances NMDAinduced increases in intracellular Ca 2+ levels and facilitates NMDA currents, but not AMPA currents; the underlying signaling mechanism involves activation of phosphoinositide 3-kinase, mitogen-activated protein kinase, and Src tyrosine kinases. 61,62 In contrast to these mechanisms, we found that the voltage-sensitive potassium channel is the target of leptin in OB neurons. This important finding provides new information about how leptin interacts with neurons in the brain.…”

2D DIGE proteomic analysis reveals fasting‐induced protein remodeling through organ‐specific transcription factor(s) in mice

“…]). Moreover, the levels of two adipose‐derived peptide hormones, leptin (the pleiotropic hormone of satiation signals/energy expenditure ) and resistin (the hormone that may ‘resist’ insulin actions ), were decreased to the same extent in F1 and F2 mice (Fig. ).…”

The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

“…After NMDARmediated calcium influx to the cytoplasm, another glutamate receptor, α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPAR), is transported from the Golgi apparatus to the cell membrane (Moult et al 2010). The transport of AMPAR exemplifies the principle of activity-dependent synaptic plasticity; LTP is mediated by AMPAR insertion into the membrane, whereas removal of AMPAR from the membrane mediates LDP (Collingridge et al 2004, McGregor & Harvey 2017.…”