Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors

Abstract Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced α-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.

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Embelin Improves the Spatial Memory and Hippocampal Long-Term Potentiation in a Rat Model of Chronic Cerebral Hypoperfusion

Scientific Reports ◽

10.1038/s41598-019-50954-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Saatheeyavaane Bhuvanendran ◽

Siti Najmi Syuhadaa Bakar ◽

Yatinesh Kumari ◽

Iekhsan Othman ◽

Mohd. Farooq Shaikh ◽

...

Keyword(s):

Synaptic Plasticity ◽

Spatial Memory ◽

Rat Model ◽

Long Term Potentiation ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Mrna Levels ◽

Post Surgery ◽

Term Potentiation

Abstract Alzheimer’s disease (AD) is the second most occurring neurological disorder after stroke and is associated with cerebral hypoperfusion, possibly contributing to cognitive impairment. In the present study, neuroprotective and anti-AD effects of embelin were evaluated in chronic cerebral hypoperfusion (CCH) rat model using permanent bilateral common carotid artery occlusion (BCCAO) method. Rats were administered with embelin at doses of 0.3, 0.6 or 1.2 mg/kg (i.p) on day 14 post-surgery and tested in Morris water maze (MWM) followed by electrophysiological recordings to access cognitive abilities and synaptic plasticity. The hippocampal brain regions were extracted for gene expression and neurotransmitters analysis. Treatment with embelin at the doses of 0.3 and 0.6 mg/kg significantly reversed the spatial memory impairment induced by CCH in rats. Embelin treatment has significantly protected synaptic plasticity impairment as assessed by hippocampal long-term potentiation (LTP) test. The mechanism of this study demonstrated that embelin treatment alleviated the decreased expression of BDNF, CREB1, APP, Mapt, SOD1 and NFκB mRNA levels caused by CCH rats. Furthermore, treatment with embelin demonstrated neuromodulatory activity by its ability to restore hippocampal neurotransmitters. Overall these data suggest that embelin improve memory and synaptic plasticity impairment in CCH rats and can be a potential drug candidate for neurodegenerative disease-related cognitive disorders.

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Citalopram Ameliorates Impairments in Spatial Memory and Synaptic Plasticity in Female 3xTgAD Mice

BioMed Research International ◽

10.1155/2017/1238687 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Zhang Wei ◽

Guo Junhong ◽

Niu Xiaoyuan ◽

Wang Jie ◽

Wang Zhaojun ◽

...

Keyword(s):

Synaptic Plasticity ◽

Spatial Memory ◽

Antidepressant Drug ◽

Amyloid Plaques ◽

Long Term Potentiation ◽

Memory Deficit ◽

Behavioral Performance ◽

Promising Strategy ◽

Term Potentiation

Alzheimer’s disease (AD) is the primary cause of dementia. There is no effective treatment. Amyloid-β peptide (Aβ) plays an important role in the pathogenesis and thus strategies suppressing Aβ production and accumulation seem promising. Citalopram is an antidepressant drug and can decrease Aβ production and amyloid plaques in transgenic mice of AD and humans. Whether citalopram can ameliorate memory deficit was not known yet. We tested the effects of citalopram on behavioral performance and synaptic plasticity in female 3xTgAD mice, a well-characterized model of AD. Mice were treated with citalopram or water from 5 months of age for 3 months. Citalopram treatment at approximately 10 mg/kg/day significantly improved spatial memory in the Morris water maze (MWM) test, while not affecting anxiety-like and depression-like behavior in 3xTgAD mice. Further, hippocampal long-term potentiation (LTP) impairment in 3xTgAD mice was reversed by citalopram treatment. Citalopram treatment also significantly decreased the levels of insoluble Aβ40 in hippocampal and cortical tissues in 3xTgAD mice, accompanied with a reduced amyloid precursor protein (APP). Together, citalopram treatment may be a promising strategy for AD and further clinical trials should be conducted to verify the effect of citalopram on cognition in patients with AD or mild cognitive impairment.

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Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.96.9.5280 ◽

1999 ◽

Vol 96 (9) ◽

pp. 5280-5285 ◽

Cited By ~ 350

Author(s):

M. E. Bach ◽

M. Barad ◽

H. Son ◽

M. Zhuo ◽

Y.-F. Lu ◽

...

Keyword(s):

Spatial Memory ◽

Signaling Pathway ◽

Late Phase ◽

Long Term Potentiation ◽

Camp Signaling ◽

Age Related ◽

Term Potentiation ◽

Camp Signaling Pathway

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Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition

Scientific Reports ◽

10.1038/s41598-021-87809-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ming Wang ◽

Gwangho Yoon ◽

Juhyun Song ◽

Jihoon Jo

Keyword(s):

Metabolic Syndrome ◽

Synaptic Plasticity ◽

Cortical Neurons ◽

High Fat Diet ◽

Neuroprotective Effect ◽

Long Term Potentiation ◽

High Fat ◽

Term Potentiation

AbstractMetabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.

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Expression of p53 Target Genes in the Early Phase of Long-Term Potentiation in the Rat Hippocampal CA1 Area

Neural Plasticity ◽

10.1155/2015/242158 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Vladimir O. Pustylnyak ◽

Pavel D. Lisachev ◽

Mark B. Shtark

Keyword(s):

Synaptic Plasticity ◽

Early Phase ◽

Target Genes ◽

P53 Protein ◽

Long Term Potentiation ◽

Protein Levels ◽

Basal Expression ◽

Term Potentiation ◽

Ca1 Area

Gene expression plays an important role in the mechanisms of long-term potentiation (LTP), which is a widely accepted experimental model of synaptic plasticity. We have studied the expression of at least 50 genes that are transcriptionally regulated by p53, as well as other genes that are related to p53-dependent processes, in the early phase of LTP. Within 30 min after Schaffer collaterals (SC) tetanization, increases in the mRNA and protein levels of Bax, which are upregulated by p53, and a decrease in the mRNA and protein levels of Bcl2, which are downregulated by p53, were observed. The inhibition of Mdm2 by nutlin-3 increased the basal p53 protein level and rescued its tetanization-induced depletion, which suggested the involvement of Mdm2 in the control over p53 during LTP. Furthermore, nutlin-3 caused an increase in the basal expression of Bax and a decrease in the basal expression of Bcl2, whereas tetanization-induced changes in their expression were occluded. These results support the hypothesis that p53 may be involved in transcriptional regulation during the early phase of LTP. We hope that the presented data may aid in the understanding of the contribution of p53 and related genes in the processes that are associated with synaptic plasticity.

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Defective synapse maturation and enhanced synaptic plasticity in Shank2-/- mice

10.1101/193078 ◽

2017 ◽

Cited By ~ 1

Author(s):

Stephanie Wegener ◽

Arne Buschler ◽

A. Vanessa Stempel ◽

Sarah A. Shoichet ◽

Denise Manahan-Vaughan ◽

...

Keyword(s):

Synaptic Plasticity ◽

Mechanistic Explanation ◽

Long Term Potentiation ◽

Autism Spectrum ◽

Term Potentiation ◽

Synapse Maturation ◽

Spectrum Disorders

SummaryAutism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic aetiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are employed for a mechanistic understanding of ASDs and the development of therapeutic strategies. In sharp contrast to all studies so far on the function of SHANK proteins, we observe enhanced synaptic plasticity in Shank2-/- mice, under various conditions in vitro and in vivo. Reproducing and extending previous results, we here present a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation (LTP) by describing a synaptic maturation deficit in Shank2-/- mice.

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Faculty Opinions recommendation of Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.9174.466655 ◽

2006 ◽

Author(s):

Robert Greenwood

Keyword(s):

Spatial Memory ◽

Memory Performance ◽

Long Term Potentiation ◽

Term Potentiation ◽

Hippocampal Ca1

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Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

Current Neurovascular Research ◽

10.2174/1567202617666200514114917 ◽

2020 ◽

Vol 17 (4) ◽

pp. 354-360 ◽

Cited By ~ 1

Author(s):

Yu-Xing Ge ◽

Ying-Ying Lin ◽

Qian-Qian Bi ◽

Yu-Juan Chen

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Synaptic Vesicle ◽

Long Term Potentiation ◽

Synaptic Dysfunction ◽

Over Expression ◽

Term Potentiation ◽

Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

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