Regulation of hippocampal synaptic function by the metabolic hormone, leptin:Implications for health and neurodegenerative disease

The role of the endocrine hormone leptin in controlling energy homeostasis in the hypothalamus are well documented. However the CNS targets for leptin are not restricted to the hypothalamus as a high density of leptin receptors are also expressed in several parts of the brain involved in higher cognitive functions including the hippocampus. Numerous studies have identified that in the hippocampus, leptin has cognitive enhancing actions as exogenous application of this hormone facilitates hippocampal-dependent learning and memory, whereas lack or insensitivity to leptin results in significant memory deficits. Leptin also markedly influences some of the main cellular changes that are involved in learning and memory including NMDA-receptor dependent synaptic plasticity and glutamate receptor trafficking. Like other metabolic hormones, there is a significant decline in neuronal sensitivity to leptin during the ageing process. Indeed, the capacity of leptin to modulate the functioning of hippocampal synapses is substantially reduced in aged compared to adult tissue. Clinical studies have also identified an association between circulating leptin levels and the risk of certain neurodegenerative disorders such as Alzheimer’s disease (AD). In view of this, targeting leptin and/or its receptor/signaling mechanisms may be an innovative approach for developing therapies to treat AD. In support of this, accumulating evidence indicates that leptin has cognitive enhancing and neuroprotective actions in various models of AD. Here we assess recent evidence that supports an important regulatory role for leptin at hippocampal CA1 synapses, and we discuss how age-related alterations in this hormonal system influences neurodegenerative disease

Leptin-based hexamers facilitate memory and prevent amyloid-driven AMPA receptor internalisation and neuronal degeneration

Datasets in support of the paper Leptin-based hexamers facilitate memory and prevent amyloid-driven AMPA receptor internalisation and neuronal degeneration These data are made available under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. https://creativecommons.org/licenses/by/4.0

Leptin: A Novel Therapeutic Target in Alzheimer's Disease?

It is well established that the hormone leptin circulates in the plasma in amounts proportional to body fat content and it regulates food intake and body weight via its actions in the hypothalamus. However, numerous studies have shown that leptin receptors are widely expressed throughout the CNS and evidence is growing that leptin plays a role in modulating a variety of neuronal processes. In particular, recent studies have highlighted a potential cognitive enhancing role for leptin as it regulates diverse aspects of hippocampal synaptic function that are thought to underlie learning and memory processes including glutamate receptor trafficking, dendritic morphology, and activity-dependent synaptic plasticity. Characterisation of the novel actions of leptin in limbic brain regions is providing valuable insights into leptin's role in higher cognitive functions in health and disease

Leptin prevents aberrant targeting of tau to hippocampal synapses via PI 3 kinase driven inhibition of GSK3β

Amyloid-β (Aβ) and hyper-phosphorylated tau are key hallmarks of Alzheimer's disease (AD), with an accumulation of both proteins linked to hippocampal synaptic dysfunction. Recent evidence indicates that Aβ drives mis-localisation of tau from axons to synapses, resulting in AMPA receptor (AMPAR) internalisation and impaired excitatory synaptic function. These tau-driven synaptic impairments are thought to underlie the cognitive deficits in AD. Consequently, limiting the synapto-toxic effects of tau may prevent AD-related cognitive deficits. Increasing evidence links leptin dysfunction with higher AD risk, and numerous studies have identified neuroprotective properties of leptin in AD models of Aβ-induced toxicity. However, it is unclear if leptin protects against tau-related synaptic dysfunction. Here we show that Aβ 1-42 significantly increases dendritic and synaptic levels of tau and p-tau in hippocampal neurons, and these effects were blocked by leptin. In accordance with GSK-3β being involved in tau phosphorylation, the protective effects of leptin involve PI 3-kinase (PI3K) activation and inhibition of GSK-3β. Aβ 1-42-driven synaptic targeting of tau was associated with the removal of GluA1-containing AMPARs from synapses, which was also inhibited by leptin-driven inhibition of GSK-3β. Direct application of oligomeric tau to hippocampal neurons caused internalisation of GluA1-containing AMPARs and this effect was blocked by prior application of leptin. Similarly, leptin prevented the ability of tau to block induction of activity-dependent long-term potentiation (LTP) at hippocampal SC-CA1 synapses. These findings increase our understanding of the neuroprotective actions of leptin in the early pre-clinical stages of AD and further validate the leptin system as a therapeutic target in AD. (Figure presented.)</p

Cholinergic pesticides cause mushroom body neuronal inactivation in honeybees

Pesticides that target cholinergic neurotransmission are highly effective, but their use has been implicated in insect pollinator population decline. Honeybees are exposed to two widely used classes of cholinergic pesticide: neonicotinoids (nicotinic receptor agonists) and orga-nophosphate miticides (acetylcholinesterase inhibitors). Although sublethal levels of neoni-cotinoids are known to disrupt honeybee learning and behaviour, the neurophysiological basis of these effects has not been shown. Here, using recordings from mushroom body Kenyon cells in acutely isolated honeybee brain, we show that the neonicotinoids imidacloprid and clothianidin, and the organophosphate miticide coumaphos oxon, cause a depolarization-block of neuronal firing and inhibit nicotinic responses. These effects are observed at concentrations that are encountered by foraging honeybees and within the hive, and are additive with combined application. Our findings demonstrate a neuronal mechanism that may account for the cognitive impairments caused by neonicotinoids, and predict that exposure to multiple pesticides that target cholinergic signalling will cause enhanced toxicity to pollinators