Publications by authors named "Zhengping Jia"

122 Publications

Norwogonin attenuates hypoxia-induced oxidative stress and apoptosis in PC12 cells.

BMC Complement Med Ther 2021 Jan 7;21(1):18. Epub 2021 Jan 7.

Department of Pharmacy, the 940th Hospital of Joint Logistics Support force of PLA, Lanzhou, 730050, Gansu, China.

Background: Norwogonin is a natural flavone with three phenolic hydroxyl groups in skeletal structure and has excellent antioxidant activity. However, the neuroprotective effect of norwogonin remains unclear. Here, we investigated the protective capacity of norwogonin against oxidative damage elicited by hypoxia in PC12 cells.

Methods: The cell viability and apoptosis were examined by MTT assay and Annexin V-FITC/PI staining, respectively. Reactive oxygen species (ROS) content was measured using DCFH-DA assay. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and antioxidant enzyme levels were determined using commercial kits. The expression of related genes and proteins was measured by real-time quantitative PCR and Western blotting, respectively.

Results: We found that norwogonin alleviated hypoxia-induced injury in PC12 cells by increasing the cell viability, reducing LDH release, and ameliorating the changes of cell morphology. Norwogonin also acted as an antioxidant by scavenging ROS, reducing MDA production, maintaining the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and decreasing the expression levels of HIF-1α and VEGF. In addition, norwogonin prevented cell apoptosis via inhibiting the expression levels of caspase-3, cytochrome c and Bax, while increasing the expression levels of Bcl-2 and the ratio of Bcl-2/Bax.

Conclusions: Norwogonin attenuates hypoxia-induced injury in PC12 cells by quenching ROS, maintaining the activities of antioxidant enzymes, and inhibiting mitochondrial apoptosis pathway.
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http://dx.doi.org/10.1186/s12906-020-03189-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791982PMC
January 2021

The Role of ADF/Cofilin in Synaptic Physiology and Alzheimer's Disease.

Front Cell Dev Biol 2020 12;8:594998. Epub 2020 Nov 12.

Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada.

Actin-depolymerization factor (ADF)/cofilin, a family of actin-binding proteins, are critical for the regulation of actin reorganization in response to various signals. Accumulating evidence indicates that ADF/cofilin also play important roles in neuronal structure and function, including long-term potentiation and depression. These are the most extensively studied forms of long-lasting synaptic plasticity and are widely regarded as cellular mechanisms underlying learning and memory. ADF/cofilin regulate synaptic function through their effects on dendritic spines and the trafficking of glutamate receptors, the principal mediator of excitatory synaptic transmission in vertebrates. Regulation of ADF/cofilin involves various signaling pathways converging on LIM domain kinases and slingshot phosphatases, which phosphorylate/inactivate and dephosphorylate/activate ADF/cofilin, respectively. Actin-depolymerization factor/cofilin activity is also regulated by other actin-binding proteins, activity-dependent subcellular distribution and protein translation. Abnormalities in ADF/cofilin have been associated with several neurodegenerative disorders such as Alzheimer's disease. Therefore, investigating the roles of ADF/cofilin in the brain is not only important for understanding the fundamental processes governing neuronal structure and function, but also may provide potential therapeutic strategies to treat brain disorders.
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http://dx.doi.org/10.3389/fcell.2020.594998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688896PMC
November 2020

The Requirement of the C-Terminal Domain of GluA1 in Different Forms of Long-Term Potentiation in the Hippocampus Is Age-Dependent.

Front Synaptic Neurosci 2020 30;12:588785. Epub 2020 Oct 30.

Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of long-lasting synaptic plasticity widely regarded as the cellular basis for learning and memory. At the CA1 synapse, there are multiple forms of LTP with distinct properties. Although AMPA glutamate receptors (AMPARs) are a key target of LTP expression, whether they are required in all forms of LTP remains unclear. To address this question, we have used our recently developed mouse line, GluA1 , where the c-terminal domain (CTD) of the endogenous GluA1 is replaced by that of GluA2. Unlike traditional GluA1 global or conditional KO mice, GluA1 mice have no changes in basal AMPAR properties or synaptic transmission allowing a better assessment of GluA1 in synaptic plasticity. We previously showed that these mice are impaired in LTP induced by high-frequency stimulation (HFS-LTP), but whether other forms of LTP are also affected in these mice is unknown. In this study, we compared various forms of LTP at CA1 synapses between GluA1 and wild-type littermates by using several induction protocols. We show that HFS-LTP is impaired in both juvenile and adult GluA1 mice. The LTP induced by theta-burst stimulation (TBS-LTP) is also abolished in juvenile GluA1 mice. Interestingly, TBS-LTP can still be induced in adult GluA1 mice, but its mechanisms are altered becoming more sensitive to protein synthesis and the extracellular signal-regulated kinase (ERK) inhibitors compared to wild type (WT) control. The GluA1 mice are also differentially altered in several forms of LTP induced under whole-cell recording paradigms. These results indicate that the CTD of GluA1 is differentially involved in different forms of LTP at CA1 synapse highlighting the complexity and adaptative potential of LTP expression mechanisms in the hippocampus.
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http://dx.doi.org/10.3389/fnsyn.2020.588785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661473PMC
October 2020

Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry.

Nat Commun 2020 07 27;11(1):3744. Epub 2020 Jul 27.

Neuroscience & Mental Health, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures. The anti-absence seizure drug ethosuximide blocks SWDs and rescues behavioral arrests and social memory impairment in the knockout mice. Restoring GABAergic transmission either by optogenetic activation of the thalamic reticular nucleus (nRT) presynaptic terminals or postsynaptic NLG2 expression in the thalamic neurons reduces the SWDs and behavioral arrests in the knockout mice. These results indicate that NLG2-mediated GABAergic transmission at the nRT-thalamic circuit represents a common mechanism underlying both epileptic seizures and ASD.
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http://dx.doi.org/10.1038/s41467-020-17560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385104PMC
July 2020

Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1 stem cells from young donors.

J Neuroinflammation 2020 Feb 7;17(1):51. Epub 2020 Feb 7.

Toronto General Hospital Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.

Background: Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy.

Methods: Here we implanted hematopoietic stem cells (HSCs) from young or old (2- or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution.

Results: Regardless of donor age, GFP cells homed to the brain of old recipients and expressed the macrophage/microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP/Iba1 cells from young and old donors were differentially polarized to an anti- and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively.

Conclusion: Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.
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http://dx.doi.org/10.1186/s12974-019-1681-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006105PMC
February 2020

Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1.

Cell Rep 2019 12;29(13):4285-4294.e5

Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

NMDA receptors (NMDARs) are critical for physiological synaptic plasticity, learning, and memory and for pathological plasticity and neuronal death. The GluN1 subunit is encoded by a single gene, GRIN1, with 8 splice variants, but whether the diversity generated by this splicing has physiological consequences remains enigmatic. Here, we generate mice lacking from the GluN1 exon 5-encoded N1 cassette (GluN1a mice) or compulsorily expressing this exon (GluN1b mice). Despite no differences in basal synaptic transmission, long-term potentiation in the hippocampus is significantly enhanced in GluN1a mice compared with that in GluN1b mice. Furthermore, GluN1a mice learn more quickly and have significantly better spatial memory performance than do GluN1b mice. In addition, in human iPSC-derived neurons in autism spectrum disorder NMDARs show characteristics of N1-lacking GluN1. Our findings indicate that alternative splicing of GluN1 is a mechanism for controlling physiological long-lasting synaptic potentiation, learning, and memory.
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http://dx.doi.org/10.1016/j.celrep.2019.11.087DOI Listing
December 2019

Protective effect of nitronyl nitroxide against hypoxia-induced damage in PC12 cells.

Biochem Cell Biol 2020 06 5;98(3):345-353. Epub 2019 Nov 5.

Department of Pharmacy, the 940th Hospital of Joint Logistics Support force of PLA, 333 Binhenan Road, Qilihe district Lanzhou, Gansu, 730050, People's Republic of China.

Hypoxia induces cellular oxidative stress that is associated with neurodegenerative diseases. HPN (4'-hydroxyl-2-substituted phenyl nitronyl nitroxide), a stable nitronyl nitroxide, has excellent free radical scavenging properties. The purpose of this study was to investigate the protective effects of HPN on hypoxia-induced damage in PC12 cells. It was shown that HPN significantly attenuated hypoxia-induced loss of cell viability, release of lactate dehydrogenase (LDH), and morphological changes in PC12 cells. Moreover, hypoxic PC12 cells had increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), and expression of HIF-1α and VEGF, but had reduced levels of superoxide dismutase (SOD) and catalase (CAT), and HPN reversed these changes. HPN also inhibited hypoxia-induced cell apoptosis via suppressing the expression of Bax, cytochrome , and caspase-3, and inducing the expression of Bcl-2. These results indicate that the protective effects of HPN on hypoxia-induced damage in PC12 cells is associated with the suppression of hypoxia-induced oxidative stress and cell apoptosis. HPN could be a promising candidate for the development of a novel neuroprotective agent.
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http://dx.doi.org/10.1139/bcb-2019-0269DOI Listing
June 2020

DNA damage and synaptic and behavioural disorders in glucose-6-phosphate dehydrogenase-deficient mice.

Redox Biol 2020 01 18;28:101332. Epub 2019 Sep 18.

Faculty of Pharmacy and Centre for Pharmaceutical Oncology, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Mice deficient in glucose-6-phosphate dehydrogenase (G6PD) cannot replenish the cellular antioxidant glutathione, which detoxifies neurodegenerative reactive oxygen species (ROS). To determine the functional consequences of G6PD deficiency, young and aging G6PD-deficient mice were evaluated for brain G6PD activity, DNA damage (comets, γH2AX), Purkinje cell loss, brain function (electrophysiology, behaviour) and lifespan. DNA comet formation was increased and Purkinje cell counts were decreased in a G6pd gene dose-dependent fashion. γH2AX formation varied by age, sex and brain region, with increased levels in G6PD-deficient young and aging females, and in aging males. Aging male G6PD-deficient mice exhibited synaptic dysfunction in hippocampal slices. G6PD-deficient young and aging females exhibited deficits in executive function, and young deficient mice exhibited deficits in social dominance. Conversely, median lifespan in G6PD-deficient females and males was enhanced. Enhanced ROS-initiated brain damage in G6PD deficiency has functional consequences, suggesting that G6PD protects against ROS-mediated neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.redox.2019.101332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812046PMC
January 2020

[Progress in cerebrospinal fluid proteome technology and its clinical application].

Sheng Wu Gong Cheng Xue Bao 2019 Sep;35(9):1643-1649

Key Laboratory of Prevention and Cure for the Plateau Environmental Damage of PLA, The 940th Hospital of PLA Joint Logistics Support Force, Lanzhou 730050, Gansu, China.

Cerebrospinal fluid surrounds and supports the central nervous system, including the ventricles and subarachnoid spaces. Cerebrospinal fluid should be an important source of biomarkers for central nervous system diseases because it is in direct contact with the central nervous system. Many studies are reported on cerebrospinal fluid proteomics, highlighting many recent progresses. Here, we review recent advances in proteomics technology and clinical application of cerebrospinal fluid.
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http://dx.doi.org/10.13345/j.cjb.190126DOI Listing
September 2019

Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy.

Am J Hum Genet 2019 09 15;105(3):534-548. Epub 2019 Aug 15.

On behalf of "United for Metabolic Diseases," 1105AZ Amsterdam, the Netherlands; Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands. Electronic address:

Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects.
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http://dx.doi.org/10.1016/j.ajhg.2019.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732527PMC
September 2019

LIMK1 and LIMK2 regulate cortical development through affecting neural progenitor cell proliferation and migration.

Mol Brain 2019 07 18;12(1):67. Epub 2019 Jul 18.

The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, 2 Sipailou Road, Nanjing, 210096, China.

LIMK1 and LIMK2 are key downstream targets to mediate the effects of the Rho family small GTPases and p21-activated kinases (PAK) in the regulation of the actin cytoskeleton. LIMKs are also critical for synaptic transmission, plasticity and memory formation. Changes in LIMK signaling are associated with several neurodevelopmental and neurodegenerative diseases, including autism, intellectual disability and Alzheimer's disease. However, the role of LIMK signaling in brain development remains unknown. In this study, we used LIMK1 KO and LIMK2 KO mice to investigate the role of LIMK signaling in the cerebral cortical development. We found that these KO mice are reduced in the number of pyramidal neurons in upper cortical layers and this reduction is accompanied by a smaller pool of neural progenitor cells and impaired neuronal migration. These results are similar to those found in PAK1 KO mice and suggest that LIMK-dependent actin regulation may play a key role in mediating the effects of PAK1 and Rho signaling in the regulation of cortical development.
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http://dx.doi.org/10.1186/s13041-019-0487-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637558PMC
July 2019

Protective effects of two novel nitronyl nitroxide radicals on heart failure induced by hypobaric hypoxia.

Life Sci 2020 May 15;248:116481. Epub 2019 May 15.

Department of Chemistry, School of Pharmacy, Fourth Military Medical University, XiAn, Shaanxi 710032, PR China. Electronic address:

Aims: Hypobaric hypoxia (HH), linked to oxidative stress, impairs cardiac function. We synthesized a novel nitronyl nitroxide radical, an HPN derivative (HEPN) and investigated the protective effects of HEPN and HPN against HH-induced heart injury in mice and the underlying mechanisms of action.

Main Methods: Mice were administered with HPN (200 mg/kg) or HEPN (200 mg/kg) 30 min before exposed to HH. The cardiac function was measured. Serum AST, CK, LDH and cTnI were estimated. Heart tissue oxidase activity, SOD, CAT, GSH-Px, ROS and MDA were estimated. ATP content, Na/K-ATPase and Ca/Mg-ATPase activity was measured. The expression of HIF-1, VEGF, Nrf2, HO-1, Bax, Bcl-2, Caspase-3 was estimated.

Key Findings: Results showed that pretreatment with HEPN or HPN led to a dramatic decrease in the activity of biochemical markers AST, CK, LDH and cTnI in murine serum. They increased the activity of SOD, CAT and GSH-Px and reduced the level of ROS and MDA in the hearts of mice. HEPN and HPN could increase the expression of Nrf2 and OH-1. They could maintain the ATPase activity. The Bax and Caspase-3 expression as well as the ratio of Bax/Bcl-2 were significantly downregulated and the Bcl-2 expression was upregulated by HPN or HEPN compared to the HH group. They may attenuate the HH-induced oxidant stress via free radical scavenging activity.

Significance: The present study showed that the nitronyl nitroxide radical HEPN and HPN may be potential therapeutic agents for treatment of HH-induced cardiac dysfunction.
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http://dx.doi.org/10.1016/j.lfs.2019.05.037DOI Listing
May 2020

Correction to: The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice.

Mol Brain 2019 01 30;12(1). Epub 2019 Jan 30.

Research Center and Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal (CIUSSS-NIM), 5400 Gouin West blvd, Montréal, QC H4J 1C5, Canada.

Correction to: Molecular Brain (2018) 11:52 https://doi.org/10.1186/s13041-018-0394-3Following publication of the original article [1], the authors reported that the article was mistakenly submitted with the omission of two authors: Feng Cao and Zhengping Jia. The authors declare that this was an error made in good faith. The corrected author list and list of affiliations are used in this Correction. The changes made to the author list and list of affiliations are also listed below, as well as the revised 'Acknowledgements' section and 'Authors' contributions' section.
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http://dx.doi.org/10.1186/s13041-019-0425-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352436PMC
January 2019

Hippocampal Long-Term Depression in the Presence of Calcium-Permeable AMPA Receptors.

Front Synaptic Neurosci 2018 13;10:41. Epub 2018 Nov 13.

Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.

The GluA2 subunit of AMPA glutamate receptors (AMPARs) has been shown to be critical for the expression of NMDA receptor (NMDAR)-dependent long-term depression (LTD). However, in young GluA2 knockout (KO) mice, this form of LTD can still be induced in the hippocampus, suggesting that LTD mechanisms may be modified in the presence of GluA2-lacking, Ca permeable AMPARs. In this study, we examined LTD at the CA1 synapse in GluA2 KO mice by using several well-established inhibitory peptides known to block LTD in wild type (WT) rodents. We showed that while LTD in the KO mice is still blocked by the protein interacting with C kinase 1 (PICK1) peptide pepEVKI, it becomes insensitive to the N-ethylmaleimide-sensitive factor (NSF) peptide pep2m. In addition, the effects of actin and cofilin inhibitory peptides were also altered. These results indicate that in the absence of GluA2, LTD expression mechanisms are different from those in WT animals, suggesting that there are multiple molecular processes enabling LTD expression that are adaptable to physiological and genetic manipulations.
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http://dx.doi.org/10.3389/fnsyn.2018.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242858PMC
November 2018

Effects of Gut Microbiota on Drug Metabolism and Guidance for Rational Drug Use Under Hypoxic Conditions at High Altitudes.

Curr Drug Metab 2019 ;20(2):155-165

School of Pharmacy, Lanzhou University, Lanzhou, 730000, Gansu, China.

Background: Modern features of drug development such as low permeability, low solubility, and improved release affect the interplay of the gut microbiota and drug metabolism. In recent years, studies have established the impact of plateau hypoxia on gut microbiota, where drug use by plateau populations is affected by hypoxia- induced changes in intestinal microflora-mediated drug metabolism.

Methods: In this review, we summarized the effects of gut microbiota on drug metabolism, and of plateau hypoxia on the intestinal flora, with the aim of providing guidance for the rational use of drugs in high-altitude populations.

Results: The evidence clearly shows that alterations in gut microbiota can affect pro-drug activation, drug inactivation, and the biotransformation of xenobiotics. Additionally, plateau hypoxia alters drug metabolism by affecting intestinal flora.

Conclusion: This review provides an overview of the effects of gut microbiota on drug metabolism and provides guidance for rational drug use under hypoxic conditions at high altitudes.
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http://dx.doi.org/10.2174/1389200219666181019145159DOI Listing
August 2019

Regulation of hippocampal long term depression by Neuroligin 1.

Neuropharmacology 2018 12 26;143:205-216. Epub 2018 Sep 26.

Neurosciences & Mental Health, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada. Electronic address:

Neuroligins (NLGs) are postsynaptic adhesion molecules known to play essential roles in synapse development and maturation, but their effects on synaptic plasticity at mature synapses remain unclear. In this study, we investigate the involvement of NLG1 in hippocampal long-term depression (LTD), a key form of long lasting synaptic plasticity, critical for memory formation and brain disorders, by using mice deficient in the expression of NLG1. We find that although NLG1 homozygous (NLG1-/-) mice show no impairments in either NMDA receptor- (NMDAR-LTD) or metabotropic glutamate receptor-dependent LTD (mGluR-LTD), the heterozygous (NLG1+/-) mice are significantly altered in both forms of LTD characterized by the absence of NMDAR-LTD but enhanced mGluR-LTD. Accordingly, the NLG1+/-, but not the NLG1-/- mice are altered in synaptic proteins, including PSD95, GluA2 and phosphorylated GluA1 at serine 845, all of which are involved in the expression of LTD. The NLG1+/- mice also exhibit autistic-like behaviors including increased grooming and impaired recognition memory. We further show that the expression of NLG3, a close family member of NLG1, is elevated in the NLG1-/-, but not in NLG1+/- mice, suggesting that the lack of LTD deficits in the NLG1-/- mice might be due to the increased NLG3. Our results reveal a gene dosage dependent role for NLG1 in the regulation of LTD and suggest that moderate changes in NLG1 protein level may be sufficient to cause synaptic and behavior deficits in brain disorders where copy number variants and hemizygosity of gene mutations are common.
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http://dx.doi.org/10.1016/j.neuropharm.2018.09.035DOI Listing
December 2018

The effect of Neuroligin-2 absence on sleep architecture and electroencephalographic activity in mice.

Mol Brain 2018 09 19;11(1):52. Epub 2018 Sep 19.

Research Center and Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal (CIUSSS-NIM), 5400 Gouin West blvd, Montréal, QC, H4J 1C5, Canada.

Sleep disorders are comorbid with most psychiatric disorders, but the link between these is not well understood. Neuroligin-2 (NLGN2) is a cell adhesion molecule that plays roles in synapse formation and neurotransmission. Moreover, NLGN2 has been associated with psychiatric disorders, but its implication in sleep remains underexplored. In the present study, the effect of Nlgn2 knockout (Nlgn2) on sleep architecture and electroencephalographic (EEG) activity in mice has been investigated. The EEG and electromyogram (EMG) were recorded in Nlgn2 mice and littermates for 24 h from which three vigilance states (i.e., wakefulness, rapid eye movement [REM] sleep, non-REM [NREM] sleep) were visually identified. Spectral analysis of the EEG was performed for the three states. Nlgn2 mice showed more wakefulness and less NREM and REM sleep compared to wild-type (Nlgn2) mice, especially during the dark period. This was accompanied by changes in the number and duration of individual episodes of wakefulness and sleep, indexing changes in state consolidation, as well as widespread changes in EEG spectral activity in all states. Abnormal 'hypersynchronized' EEG events have also been observed predominantly in Nlgn2 mice. These events were mainly observed during wakefulness and REM sleep. In addition, Nlgn2 mice showed alterations in the daily time course of NREM sleep delta (1-4 Hz) activity, pointing to modifications in the dynamics of sleep homeostasis. These data suggest that NLGN2 participates in the regulation of sleep duration as well as EEG activity during wakefulness and sleep.
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http://dx.doi.org/10.1186/s13041-018-0394-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146600PMC
September 2018

PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior.

Cell Rep 2018 08;24(8):2029-2041

Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China; University of the Chinese Academy of Sciences, Beijing 100049, China; Institute of Genomic Medicine, Wenzhou Medical College, Wenzhou 325000, China. Electronic address:

Synaptic cytoskeleton dysfunction represents a common pathogenesis in neurodevelopmental disorders, such as autism spectrum disorder (ASD). The serine/threonine kinase PAK2 is a critical regulator of cytoskeleton dynamics. However, its function within the central nervous system and its role in ASD pathogenesis remain undefined. Here, we found that Pak2 haploinsufficiency resulted in markedly decreased synapse densities, defective long-term potentiation, and autism-related behaviors in mice. Phosphorylation levels of key actin regulators LIMK1 and cofilin, together with their mediated actin polymerization, were reduced in Pak2mice. We identified one de novo PAK2 nonsense mutation that impaired PAK2 function in vitro and in vivo and four de novo copy-number deletions containing PAK2 in large cohorts of patients with ASD. PAK2 deficiency extensively perturbed functional networks associated with ASD by regulating actin cytoskeleton dynamics. Our genetic and functional results demonstrate a critical role of PAK2 in brain development and autism pathogenesis.
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http://dx.doi.org/10.1016/j.celrep.2018.07.061DOI Listing
August 2018

Kcnj6(GIRK2) trisomy is not sufficient for conferring the susceptibility to infantile spasms seen in the Ts65Dn mouse model of down syndrome.

Epilepsy Res 2018 09 12;145:82-88. Epub 2018 Jun 12.

Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Canada; Department of Pediatrics, Faculty of Medicine, University of Toronto, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Canada; Neuroscience and Mental Health program, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Canada.

Objective: Infantile spasms (IS) is a catastrophic childhood seizure disorder that is characterized by extensor and/or flexor spasms, cognitive deterioration and a characteristic EEG abnormality. The latter consists of a pattern of a spike-wave followed by an electrodecremental response (EDR), which is a flattening of the EEG waveform amplitude. The mechanism/circuitry that underpins IS is unknown. Children with Down Syndrome (DS) are particularly vulnerable to IS. The standard mouse model of DS is the Ts65Dn mutant mouse (Ts). Using the Ts mouse, we have created an animal model of IS in DS. This model entails the treatment of Ts mice with a GABAR agonist with a resultant recapitulation of the semiological, electrographic, and pharmacological phenotype of IS. One of the genes triplicated in Ts mice is the kcnj6 gene which codes for the G-protein inwardly rectifying potassium channel 2 (GIRK2) protein. We have shown that over expression of GIRK2 in Ts brain is necessary for the production of the GABAR agonist induced IS phenotype in the Ts mouse. Here, we ask the question whether the excess GIRK2 is sufficient for the production of the GABAR agonist induced IS phenotype.

Methods: To address this question, we used kcnj6 triploid mice, and compared the number of spasms via video analysis and EDR events via EEG to that of the WT mice.

Results: We now show that GABAR agonist-treated kcnj6 triploid mice failed to show susceptibility to the IS phenotype. Therefore, over expression of GIRK2 in the brain is necessary, but not sufficient to confer susceptibility to the GABAR agonist-induced IS phenotype in the Ts model of DS.

Significance: It is therefore likely that GIRK2 is working in concert with another factor or factors that are altered in the Ts brain in the production of the GABAR agonist-induced IS phenotype.
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http://dx.doi.org/10.1016/j.eplepsyres.2018.06.006DOI Listing
September 2018

Crucial Role of Postsynaptic Syntaxin 4 in Mediating Basal Neurotransmission and Synaptic Plasticity in Hippocampal CA1 Neurons.

Cell Rep 2018 06;23(10):2955-2966

Division of Fundamental Neurobiology, Krembil Research Institute, University Health Network, Toronto, ON M5T 2S8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Trafficking of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity, yet the underlying mechanisms remain elusive. Here, we investigated the role of syntaxin 4 in postsynaptic hippocampal CA1 neurons by analyzing conditional knockout (syntaxin 4 cKO) mice. We show that syntaxin 4 cKO resulted in reduction of basal neurotransmission without changes in paired-pulse ratios. Both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor-mediated charge transfers were diminished. Patch-clamp experiments revealed that amplitudes, but not frequencies, of spontaneous excitatory postsynaptic currents are reduced. Syntaxin 4 knockout (KO) caused drastic reduction in expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors in cultured hippocampal neurons. Furthermore, cKO caused defects in theta-burst stimulation induced long-term potentiation and spatial learning as assessed by a water maze task, indicating that synaptic plasticity was altered. Our data reveal a crucial role of syntaxin 4 in trafficking of ionotropic glutamate receptors that are essential for basal neurotransmission, synaptic plasticity, and spatial memory.
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http://dx.doi.org/10.1016/j.celrep.2018.05.026DOI Listing
June 2018

Activation of Entorhinal Cortical Projections to the Dentate Gyrus Underlies Social Memory Retrieval.

Cell Rep 2018 05;23(8):2379-2391

Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Social interactions are essential to our mental health, and a deficit in social interactions is a hallmark characteristic of numerous brain disorders. Various subregions within the medial temporal lobe have been implicated in social memory, but the underlying mechanisms that tune these neural circuits remain unclear. Here, we demonstrate that optical activation of excitatory entorhinal cortical perforant projections to the dentate gyrus (EC-DG) is necessary and sufficient for social memory retrieval. We further show that inducible disruption of p21-activated kinase (PAK) signaling, a key pathway important for cytoskeletal reorganization, in the EC-DG circuit leads to impairments in synaptic function and social recognition memory, and, importantly, optogenetic activation of the EC-DG terminals reverses the social memory deficits in the transgenic mice. These results provide compelling evidence that activation of the EC-DG pathway underlies social recognition memory recall and that PAK signaling may play a critical role in modulating this process.
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http://dx.doi.org/10.1016/j.celrep.2018.04.073DOI Listing
May 2018

Plateau hypoxia attenuates the metabolic activity of intestinal flora to enhance the bioavailability of nifedipine.

Drug Deliv 2018 Nov;25(1):1175-1181

a School of Pharmacy , Lanzhou University , Lanzhou , China.

Nifedipine is completely absorbed by the gastrointestinal tract and its pharmacokinetics and metabolism may be influenced by microorganisms. If gut microbes are involved in the metabolism of nifedipine, plateau hypoxia may regulate the bioavailability and the therapeutic effect of nifedipine by altering the metabolic activity of the gut microbiota. We herein demonstrated for the first time that gut flora is involved in the metabolism of nifedipine by in vitro experiments. In addition, based on the results of 16S rRNA analysis of feces in rats after acute plateau, we first confirmed that the plateau environment could cause changes in the number and composition of intestinal microbes. More importantly, these changes in flora could lead to a slower metabolic activity of nifedipine in the body after an acute plateau, resulting in increased bioavailability and therapeutic efficacy of nifedipine. Our research will provide basis and new ideas for changes in the fecal flora of human acutely entering the plateau, and contribute to rational drug use of nifedipine.
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http://dx.doi.org/10.1080/10717544.2018.1469687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058681PMC
November 2018

Publisher Correction: The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning.

Nat Neurosci 2018 Oct;21(10):1494

Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.

In the version of this article initially published, the wrong version of Supplementary Fig. 10 was posted and the city for affiliation 4, the Co-innovation Center of Neuroregeneration, Nantong University, was given as Nanjing instead of Nantong. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41593-018-0116-2DOI Listing
October 2018

[Role of drug transporters in rational use of drugs 
at high altitude area].

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2018 Mar;43(3):327-332

Department of Pharmacy, General Hospital of Xining Logistic Support Center, Lanzhou 730050, China.

Pharmacokinetics plays a key role in rational use of medicines. Many factors can affect the drug's pharmacokinetics. Previous studies mainly focused on the impact of hypoxia on hepatic drug metabolizing enzyme, but uncommon on drug transporters. Actually, drug transporter is a key factor for activation of the drugs transport across the cell membrane into the inside of cells, such as multidrug resistance protein (MDR), breast cancer resistance protein (BCRP), multidrug resistance associated protein (MRP), organic cation transporter (OCT), organic anion-transporting polypeptide (OATP), organic anion transporter (OAT), qligopeptide transporter (PEPT), etc. They are widely present in the small intestine villus epithelial cells, renal tubular epithelial cells, hepatocytes and biliary epithelial cells. They play a very important role in drug absorption, distribution, metabolism and excretion. The changes in drug transporters under hypoxia in intestinal could affect the bioavailability of drugs; the changes in drug transporters in organs could affect drug's distribution, subsequent drug's indications and adverse reactions; the changes in drug transporters in liver and kidney could affect the metabolism and excretion rate of drugs, thereby the drug's residence time and half-life.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2018.03.015DOI Listing
March 2018

Expression profile of microRNAs in expressed prostatic secretion of healthy men and patients with IIIA chronic prostatitis/chronic pelvic pain syndrome.

Oncotarget 2018 Feb 6;9(15):12186-12200. Epub 2018 Jan 6.

Department of Urology, Lanzhou General Hospital of Lanzhou Command, Lanzhou, China.

The current study aimed to identify a comprehensive expression-profile of microRNAs (miRNAs) in expressed prostatic secretion (EPS) collected from healthy men and patients with CP/CPPS (Chronic prostatitis/Chronic pelvic pain syndrome). After clinical screening of 382 participants, 60 healthy men and 59 IIIA CP/CPPS patients with significant pelvic-pain were included into this study from March 2012 to December 2014. High-throughput sequencing was employed to identify characteristic expression-profile of EPS-miRNAs. QRT-PCR was further performed to confirm elevated levels of differential EPS-miRNAs. Finally, candidate EPS-miRNAs were measured traceably in 21 follow-up patients and their classify-accuracy on IIIA CP/CPPS were analyzed by ROC (receiver operating characteristic) curve. In discovery-phage, 41 and 43 predominant EPS-miRNAs were found in pooled EPS-sample from 40 healthy men and 39 IIIA CP/CPPS patients, respectively. Furthermore, 22 abundant EPS-miRNAs were up-regulated with ≥ 2-fold in 20 patients compared to 20 healthy men. In testing-phage, elevated levels of miR-21-5p, miR-30a-5p, miR-30d-5p, miR-103a-3p and miR-141-3p were further confirmed in 33 patients by comparing to 30 healthy men. In validation-phage, relieved pelvic-pain symptom of 21 follow-up patients was found to be accompanied by significant down-regulation of miR-21-5p, miR-103a-3p and miR-141-3p. Particularly, ROC curve analysis indicated the highest area under ROC curve (AUC) was found for miR-21-5p (0.891), followed in order by miR-141-3p and miR-103a-3p. Our studies provided evidence that secretory miRNAs existed in EPS and dysregulated EPS-miRNAs were associated with prostatitis. In particular, miR-21-5p possessed a high classify-accuracy for IIIA CP/CPPS patients with significant pelvic pain.
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http://dx.doi.org/10.18632/oncotarget.24069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844738PMC
February 2018

Neurexin-Neuroligin 1 regulates synaptic morphology and functions via the WAVE regulatory complex in neuromuscular junction.

Elife 2018 03 14;7. Epub 2018 Mar 14.

Institute of Life Sciences, the Collaborative Innovation Center for Brain Science, Southeast University, Nanjing, China.

Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.
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http://dx.doi.org/10.7554/eLife.30457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873926PMC
March 2018

Plasma proteomic study of acute mountain sickness susceptible and resistant individuals.

Sci Rep 2018 01 19;8(1):1265. Epub 2018 Jan 19.

Key Laboratory of the plateau of environmental damage control, Lanzhou General Hospital of Lanzhou Military Command, No. 333 Binhe South Road, Lanzhou, 730050, Gansu, China.

Although extensive studies have focused on the development of acute mountain sickness (AMS), the exact mechanisms of AMS are still obscure. In this study, we used isobaric tags for relative and absolute quantitation (iTRAQ) proteomic analysis to identify novel AMS-associated biomarkers in human plasma. After 9 hours of hypobaric hypoxia the abundance of proteins related to tricarboxylic acid (TCA) cycle, glycolysis, ribosome, and proteasome were significantly reduced in AMS resistant (AMS-) group, but not in AMS susceptible (AMS+) group. This suggested that AMS- individuals could reduce oxygen consumption via repressing TCA cycle and glycolysis, and reduce energy consumption through decreasing protein degradation and synthesis compared to AMS+ individuals after acute hypoxic exposure. The inflammatory response might be decreased resulting from the repressed TCA cycle. We propose that the ability for oxygen consumption reduction may play an important role in the development of AMS. Our present plasma proteomic study in plateau of the Han Chinese volunteers gives new data to address the development of AMS and potential AMS correlative biomarkers.
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http://dx.doi.org/10.1038/s41598-018-19818-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775437PMC
January 2018

Acute and sub-chronic toxicological studies of the iridoid glycosides extract of Lamiophlomis rotata (Benth.) Kudo in rats.

Regul Toxicol Pharmacol 2018 Feb 26;92:315-323. Epub 2017 Dec 26.

School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, PR China. Electronic address:

Lamiophlomis rotata(Benth.) Kudo is widely used in traditional Chinese medicine and its iridoid glycosides extract (IGLR) was the main active ingredient with hemostatic, antinociceptive and anti-inflammatory effects. This study was aimed to evaluate the safety of IGLR using acute and sub-chronic toxicity study methods on Sprague-Dawley rats. In acute toxicity test, IGLR caused slight diarrhea in three dose groups and a decreased of RBC and increased of MCH and Ret (P < .05) were observed in 16 g/kg group. In sub-chronic toxicity study, unscheduled deaths occurred in 1 and 3 rats at 0.40 and 1.00 g/kg groups, respectively. A slight diarrhea was observed in 1.00 g/kg group. Hemolytic anemia was the main toxicity effects of IGLR found in 0.40 and 1.00 g/kg groups, with a significant decrease of RBC, HGB (P < .05) and increase of Ret, MCV, MCH (P < .05) in hematological parameters, a significant decrease of ALT, Crea (P < .05) and increase of TBIL (P < .05) in biochemical parameters, and a significant increase of the percentage of rubricyte, normoblast (P < .05) in bone marrow. Overall, this study found IGLR has a potential toxicity considering with hemolytic anemia and diarrhea to rat. These results provide an important reference for further IGLR-related drug exploration.
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http://dx.doi.org/10.1016/j.yrtph.2017.12.018DOI Listing
February 2018

The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning.

Nat Neurosci 2018 01 11;21(1):50-62. Epub 2017 Dec 11.

Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada.

Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS.
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http://dx.doi.org/10.1038/s41593-017-0030-zDOI Listing
January 2018

Regulation of Neurotransmitter Release by Amyloid Precursor Protein Through Synapsin Phosphorylation.

Neurochem Res 2019 Mar 19;44(3):683-691. Epub 2017 Oct 19.

Neurosciences & Mental Health, the Hospital for Sick Children, 555 University Ave., Toronto, ON, M5G 1X8, Canada.

Abnormal processing of amyloid precursor protein (APP) and aggregation of the Aβ peptide are known to play a key role in the pathogenesis of Alzheimer disease, but the function of endogenous APP under normal physiological conditions remains poorly understood. In this study, we investigated presynaptic changes in APP knockout (KO) mice. We demonstrate that both sucrose-induced neurotransmission and synaptic depletion in response to high frequency stimulation are significantly enhanced in APP KO compared to wild type littermates. In addition, the level of phosphorylated forms of synapsins, but not total synapsins, is elevated in the KO mice. Furthermore, we show that the inhibition of L-type calcium channels normalizes phosphorylated synapsins and slows down the high frequency induced synaptic depletion in APP KO mice. These results suggest a new mechanism by which APP regulates synaptic vesicle dynamics through synapsin-dependent phosphorylation.
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http://dx.doi.org/10.1007/s11064-017-2418-2DOI Listing
March 2019