A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions
          of Leptin

Malekizadeh, Yasaman; Holiday, Alison; Redfearn, Devon; Ainge, James A.; Doherty, Gayle H.; Harvey, Jenni

doi:10.1093/cercor/bhw272

Cited by 32 publications

(71 citation statements)

References 51 publications

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“…Intensity of staining was determined off‐line by Lasersharp software (Zeiss). Analysis lines (50 μm) were drawn along randomly selected dendritic regions, and mean fluorescence intensity for GluA1 (13, 26, 27), phosphorylated‐JAK2 or phosphorylated‐STAT3 surface staining was calculated for each dendrite. For synaptic colocalization experiments, surface GluA1 and anti‐PSD‐95 dendritic immunostaining were compared.…”

Section: Methodsmentioning

confidence: 99%

“…For inhibitor experiments, neurons were pretreated with inhibitor for 30 min before NMDA. To label surface GluA1, living neurons were incubated with an antibody against the N-terminal region of GluA1 [sheep anti-GluA1; in-house antibody against synthetic peptide (RTSDSRDHTRVDWKR) corresponding to residues 253-267 of GluA1; 1:100 (24)] at 4°C (13,(25)(26)(27). Cultures were then fixed with 4% paraformaldehyde (5 min).…”

Section: Immunocytochemistrymentioning

confidence: 99%

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Canonical JAK‐STAT signaling is pivotal for long‐term depression at adult hippocampal temporoammonic‐CA1 synapses

2017

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The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is involved in numerous cellular processes and it is implicated in neurodegenerative disorders, like Alzheimer disease. Recent studies identified a crucial role for this pathway in activity-dependent long-term depression (LTD) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, it is unclear whether JAK-STAT signaling also regulates excitatory synaptic function at the anatomically distinct temporoammonic (TA) input to CA1 neurons. Here we demonstrate that LTD at adult TA-CA1 synapses involves JAK-STAT signaling, but unlike SC-CA1 synapses, requires rapid gene transcription. TA-CA1 LTD requires NMDA receptor activation and is independent of PI3K or ERK signaling. JAK-STAT signaling was critical for TA-CA1 LTD as inhibition of JAK or STAT blocked LTD induction and prevented NMDA-induced AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor internalization in hippocampal neurons. Moreover, an increase in phosphorylated JAK2 and STAT3 accompanied chemical induction of LTD and AMPA receptor internalization. STAT3-driven gene transcription was required for LTD as inhibition of STAT3-DNA binding, nuclear export, and gene transcription all prevented LTD induction. These data indicate an essential role for canonical JAK-STAT signaling in activity-dependent LTD at TA-CA1 synapses and provide valuable insight into the role of the TA input in hippocampal synaptic plasticity.-McGregor, G., Irving, A. J., Harvey, J. Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses.

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Section: Methodsmentioning

confidence: 99%

Section: Immunocytochemistrymentioning

confidence: 99%

Canonical JAK‐STAT signaling is pivotal for long‐term depression at adult hippocampal temporoammonic‐CA1 synapses

2017

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“…The TA input is also implicated in episodic memory processes as this pathway has been shown to integrate cortical and place cell information (Stokes et al, 2015). Recent evidence indicates that leptin regulates episodic-like memory, as leptin improves performance in object-place-context recognition tasks that model human episodic memory (Malekizadeh et al, 2017). Thus, as leptin potently regulate synaptic efficacy at TA-CA1 synapses, it is feasible that the modulatory actions of leptin at TA-CA1 synapses play a prominent role in influencing not only memory consolidation and place cell activity, but also episodic memory.…”

Section: Age-dependent Regulation Of Excitatory Synaptic Transmissionmentioning

confidence: 99%

“…Indeed, recent studies have identified that one particular leptin fragment, leptin (116-130) not only enhances the cellular events underlying learning and memory, but it also prevents the aberrant effects of Aβ on hippocampal synaptic plasticity in acute brain slices and AMPA receptor trafficking in hippocampal neurons (Malekizadeh et al, 2017); effects that parallel the actions of the whole leptin molecule (Doherty et al, 2013). These findings raise the interesting possibility that leptin (116-130) may have therapeutic potential in AD, although this remains to be determined in clinical studies.…”

Section: Leptin Protects Against the Acute Effects Of Aβ On Hippocampmentioning

confidence: 99%

Food for thought: Leptin regulation of hippocampal function and its role in Alzheimer's disease

McGregor

Harvey

2018

Neuropharmacology

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Accumulating evidence indicates that diet and body weight are important factors associated with Alzheimer's disease (AD), with a significant increase in AD risk linked to mid-life obesity, and weight loss frequently occurring in the early stages of AD. This has fuelled interest in the hormone leptin, as it is an important hypothalamic regulator of food intake and body weight, but leptin also markedly influences the functioning of the hippocampus; a key brain region that degenerates in AD. Increasing evidence indicates that leptin has cognitive enhancing properties as it facilitates the cellular events that underlie hippocampal-dependent learning and memory. However, significant reductions in leptin's capacity to regulate hippocampal synaptic function occurs with age and dysfunctions in the leptin system are associated with an increased risk of AD. Moreover, leptin is a potential novel target in AD as leptin treatment has beneficial effects in various models of AD. Here we summarise recent advances in leptin neurobiology with particular focus on regulation of hippocampal synaptic function by leptin and the implications of this for neurodegenerative disorders like AD. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

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“…Thus, application of leptin rescues Aβ-induced inhibition of LTP and facilitation of LTD [98,99]. Furthermore, treatment with leptin prevents Aβ-driven internalisation of the AMPA receptor subunit, GluA1 [98,99]. In addition to preventing the acute effects of Aβ, leptin also protects against the chronic actions of Aβ that result in neuronal Table 1 Summary of the age-dependent and bi-directional effects of leptin on synaptic efficacy at TA-and SC-CA1 synapses Summary table highlighting the divergent actions of leptin at hippocampal TA-CA1 and SC-CA1 synapses.…”

Section: A Link Between Leptin and Alzheimer's Disease (Ad)mentioning

confidence: 99%

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

McGregor

Harvey

2017

Neurochem Res

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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.

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A Leptin Fragment Mirrors the Cognitive Enhancing and Neuroprotective Actions of Leptin

Cited by 32 publications

References 51 publications

Canonical JAK‐STAT signaling is pivotal for long‐term depression at adult hippocampal temporoammonic‐CA1 synapses

Canonical JAK‐STAT signaling is pivotal for long‐term depression at adult hippocampal temporoammonic‐CA1 synapses

Food for thought: Leptin regulation of hippocampal function and its role in Alzheimer's disease

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

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