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Philosophical Transactions of the Royal... Jul 2024The family of SHANK proteins have been shown to be critical in regulating glutamatergic synaptic structure, function and plasticity. variants are also prevalent in...
The family of SHANK proteins have been shown to be critical in regulating glutamatergic synaptic structure, function and plasticity. variants are also prevalent in autism spectrum disorders (ASDs), where glutamatergic synaptopathology has been shown to occur in multiple ASD mouse models. Our previous work has shown that dietary zinc in and ASD mouse models can reverse or prevent ASD behavioural and synaptic deficits. Here, we have examined whether dietary zinc can influence behavioural and synaptic function in mice. Our data show that dietary zinc supplementation can reverse hyperactivity and social preference behaviour in mice, but it does not alter deficits in working memory. Consistent with this, at the synaptic level, deficits in NMDA/AMPA receptor-mediated transmission are also not rescued by dietary zinc. In contrast to other ASD models examined, we observed that SHANK3 protein was highly expressed at the synapses of mice and that dietary zinc returned these to wild-type levels. Overall, our data show that dietary zinc has differential effectiveness in altering ASD behaviours and synaptic function across ASD mouse models even within the family. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Zinc; Nerve Tissue Proteins; Mice, Knockout; Mice; Dietary Supplements; Autism Spectrum Disorder; Disease Models, Animal; Male; Behavior, Animal; Autistic Disorder; Microfilament Proteins; Mice, Inbred C57BL
PubMed: 38853567
DOI: 10.1098/rstb.2023.0230 -
Philosophical Transactions of the Royal... Jul 2024Alternative splicing of exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1...
Alternative splicing of exon 5 regulates induction of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses: LTP in mice lacking the GluN1 exon 5-encoded N1 cassette (GluN1a mice) is significantly increased compared with that in mice compulsorily expressing this exon (GluN1b mice). The mechanism underlying this difference is unknown. Here, we report that blocking the non-receptor tyrosine kinase Src prevents induction of LTP in GluN1a mice but not in GluN1b. We find that activating Src enhances pharmacologically isolated synaptic -methyl-d-aspartate receptor (NMDAR) currents in GluN1a mice but not in GluN1b. Moreover, we observe that Src activation increases the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor component of Schaffer collateral-evoked excitatory post-synaptic potentials in GluN1a mice, but this increase is prevented by blocking NMDARs. We conclude that at these synapses, NMDARs in GluN1a mice are subject to upregulation by Src that mediates induction of LTP, whereas NMDARs in GluN1b mice are not regulated by Src, leading to Src-resistance of LTP. Thus, we have uncovered that a key regulatory mechanism for synaptic potentiation is gated by differential splicing of exon 5 of . This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Long-Term Potentiation; Alternative Splicing; Receptors, N-Methyl-D-Aspartate; Mice; Exons; src-Family Kinases; Nerve Tissue Proteins; Male; Synapses; Mice, Inbred C57BL
PubMed: 38853562
DOI: 10.1098/rstb.2023.0236 -
Philosophical Transactions of the Royal... Jul 2024The roles of Ca-induced calcium release in synaptic plasticity and metaplasticity are poorly understood. The present study has addressed the role of intracellular Ca...
The roles of Ca-induced calcium release in synaptic plasticity and metaplasticity are poorly understood. The present study has addressed the role of intracellular Ca stores in long-term potentiation (LTP) and a form of heterosynaptic metaplasticity known as synaptic tagging and capture (STC) at CA1 synapses in mouse hippocampal slices. The effects of two compounds, ryanodine and cyclopiazonic acid (CPA), were examined on LTP induced by three distinct induction protocols: weak (w), compressed (c) and spaced (s) theta-burst stimulation (TBS). These compounds did not significantly affect LTP induced by the wTBS (one episode of TBS; 25 stimuli) or cTBS (three such episodes with a 10 s inter-episode interval (IEI); 75 stimuli) but substantially inhibited LTP induced by a sTBS (10 min IEI; 75 stimuli). Ryanodine and CPA also prevented a small heterosynaptic potentiation that was observed with the sTBS protocol. Interestingly, these compounds also prevented STC when present during either the sTBS or the subsequent wTBS, applied to an independent input. All of these effects of ryanodine and CPA were similar to that of a calcium-permeable AMPA receptor blocker. In conclusion, Ca stores provide one way in which signals are propagated between synaptic inputs and, by virtue of their role in STC, may be involved in associative long-term memories. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Long-Term Potentiation; Mice; Synapses; Ryanodine; Calcium; Indoles; Hippocampus; Mice, Inbred C57BL; Neuronal Plasticity; CA1 Region, Hippocampal; Male
PubMed: 38853556
DOI: 10.1098/rstb.2023.0241 -
Philosophical Transactions of the Royal... Jul 2024Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about...
Synaptic plasticity is a key cellular model for learning, memory and chronic pain. Most previous studies were carried out in rats and mice, and less is known about synaptic plasticity in non-human primates. In the present study, we used integrative experimental approaches to study long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of adult tree shrews. We found that glutamate is the major excitatory transmitter and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid (AMPA) receptors mediate postsynaptic responses. LTP in tree shrews was greater than that in adult mice and lasted for at least 5 h. -methyl-d-aspartic acid (NMDA) receptors, Ca influx and adenylyl cyclase 1 (AC1) contributed to tree shrew LTP. Our results suggest that LTP is a major form of synaptic plasticity in the ACC of primate-like animals. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Long-Term Potentiation; Gyrus Cinguli; Tupaiidae; Mice; Receptors, N-Methyl-D-Aspartate; Receptors, AMPA; Adenylyl Cyclases; Glutamic Acid; Male
PubMed: 38853555
DOI: 10.1098/rstb.2023.0240 -
Adiponectin rescues synaptic plasticity in the dentate gyrus of a mouse model of Fragile X Syndrome.Philosophical Transactions of the Royal... Jul 2024Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients...
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Animals; Fragile X Syndrome; Dentate Gyrus; Mice; Neuronal Plasticity; Mice, Knockout; Disease Models, Animal; Fragile X Mental Retardation Protein; Adiponectin; Long-Term Potentiation; Male; Receptors, AMPA
PubMed: 38853554
DOI: 10.1098/rstb.2023.0221 -
Philosophical Transactions of the Royal... Jul 2024This review focuses on the activity-dependent diffusion trapping of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as a crucial mechanism for... (Review)
Review
This review focuses on the activity-dependent diffusion trapping of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as a crucial mechanism for the expression of early long-term potentiation (LTP), a process central to learning and memory. Despite decades of research, the precise mechanisms by which LTP induction leads to an increase in AMPAR responses at synapses have been elusive. We review the different hypotheses that have been put forward to explain the increased AMPAR responsiveness during LTP. We discuss the dynamic nature of AMPAR complexes, including their constant turnover and activity-dependent modifications that affect their synaptic accumulation. We highlight a hypothesis suggesting that AMPARs are diffusively trapped at synapses through activity-dependent interactions with protein-based binding slots in the post-synaptic density (PSD), offering a potential explanation for the increased synaptic strength during LTP. Furthermore, we outline the challenges still to be addressed before we fully understand the functional roles and molecular mechanisms of AMPAR dynamic nanoscale organization in LTP. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Topics: Long-Term Potentiation; Receptors, AMPA; Animals; Synapses; Diffusion; Humans; Post-Synaptic Density
PubMed: 38853553
DOI: 10.1098/rstb.2023.0220 -
Phytomedicine : International Journal... Aug 2024Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of...
Zexieyin formula alleviates Alzheimer's disease via post-synaptic CaMKII modulating AMPA receptor: Involved in promoting neurogenesis to strengthen synaptic plasticity in mice hippocampus.
BACKGROUND
Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD.
PURPOSE
The study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action.
METHODS
We used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD.
RESULTS
The results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells.
CONCLUSION
ZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.
Topics: Animals; Alzheimer Disease; Receptors, AMPA; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Drugs, Chinese Herbal; Hippocampus; Neurogenesis; Disease Models, Animal; Mice; Male; Neuronal Plasticity; Scopolamine; Mice, Transgenic; Maze Learning; Donepezil; Cyclic AMP Response Element-Binding Protein; Memory; Mice, Inbred C57BL
PubMed: 38852473
DOI: 10.1016/j.phymed.2024.155802 -
Journal of Labelled Compounds &... Jun 2024A new automated radiosynthesis of [C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([C]K2), a radiopharmaceutical for the glutamate...
Improved Radiosynthesis and Automation of [C]2-(2,6-Difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([C]K2) for Positron Emission Tomography of the Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptor.
A new automated radiosynthesis of [C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use.
PubMed: 38845124
DOI: 10.1002/jlcr.4113 -
Psychopharmacology Jun 2024Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current...
Ellagic Acid Reverses Alterations in the Expression of AMPA Receptor and Its Scaffolding Proteins in the Cerebral Cortex and Memory Decline in STZ-sporadic Alzheimer' s Disease Mouse Model.
RATIONALE
Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current therapeutic approaches for the amelioration of the anomalies of AD are not effective.
OBJECTIVE
In the present study, the molecular mechanisms underlying sporadic AD (sAD), the memory related behavioral analysis and neuroprotective effects of Ellagic acid (EA) were investigated.
METHOD
sAD mouse model was developed by intracerebroventricular (ICV) injection of Streptozotocin (STZ). The efficacy of EA, a naturally occurring polyphenol, in amelioration of anomalies associated with sAD was assessed. EA was administered once daily for 28 days at a dose of 75 mg/kg body weight followed by neurobehavioral, biochemical, molecular and neuronal count analysis to delineate the mode of action of EA.
RESULT
The ICV injection of STZ in mice significantly increased the expression of AD biomarkers in addition to enhanced oxidative stress. A decline in the discrimination index in Novel Object Recognition Test was observed indicating the compromise of recognition memory in AD. Studies on the expression of genes involved in synaptic plasticity reveal the dysregulation of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) of the glutamate and its scaffolding proteins in the postsynaptic density and thereby synaptic plasticity in AD. ICV-STZ led to significant upregulation of apoptotic markers which led to decrease in neuronal density of the cerebral cortex. EA significantly reversed the above and improved anomalies of sAD.
CONCLUSION
EA was observed to profoundly modulate the genes involved in AD pathophysiology, restored antioxidant enzymes activity, reduced lipid peroxidation and neuronal loss in the sAD brain. Further, EA was observed to effectively modulate the genes involved in apoptosis and synaptic plasticity. Therefore, EA possesses promising anti-AD properties, which may improve AD-associated anomalies by modulating synaptic plasticity via AMPAR signaling.
PubMed: 38842699
DOI: 10.1007/s00213-024-06622-9 -
The Journal of Neuroscience : the... Jun 2024A decade ago, in 2013, and over the course of 4 summer months, three separate observations were reported that each shed light independently on a new molecular... (Review)
Review
A decade ago, in 2013, and over the course of 4 summer months, three separate observations were reported that each shed light independently on a new molecular organization that fundamentally reshaped our perception of excitatory synaptic transmission (Fukata et al., 2013; MacGillavry et al., 2013; Nair et al., 2013). This discovery unveiled an intricate arrangement of AMPA-type glutamate receptors and their principal scaffolding protein PSD-95, at synapses. This breakthrough was made possible, thanks to advanced super-resolution imaging techniques. It fundamentally changed our understanding of excitatory synaptic architecture and paved the way for a brand-new area of research. In this Progressions article, the primary investigators of the nanoscale organization of synapses have come together to chronicle the tale of their discovery. We recount the initial inquiry that prompted our research, the preceding studies that inspired our work, the technical obstacles that were encountered, and the breakthroughs that were made in the subsequent decade in the realm of nanoscale synaptic transmission. We review the new discoveries made possible by the democratization of super-resolution imaging techniques in the field of excitatory synaptic physiology and architecture, first by the extension to other glutamate receptors and to presynaptic proteins and then by the notion of trans-synaptic organization. After describing the organizational modifications occurring in various pathologies, we discuss briefly the latest technical developments made possible by super-resolution imaging and emerging concepts in synaptic physiology.
Topics: Receptors, AMPA; Synapses; Animals; Humans; Synaptic Transmission; Nanostructures
PubMed: 38839340
DOI: 10.1523/JNEUROSCI.2104-23.2024