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Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway.

ABSTRACT: It is not known whether brain?derived neurotrophic factor (BDNF) protects hippocampal neurons from high glucose?induced apoptosis and/or synaptic plasticity dysfunction. The present study aimed to assess whether BDNF exerted a neuroprotective effect in rat hippocampal neurons exposed to high glucose and examine the underlying mechanisms. The apoptosis of primary hippocampal neurons was assessed by Annexin V?fluorescein isothiocyanate/propidium iodide staining. The mRNA and protein expression levels were measured by reverse transcription?-quantitative polymerase chain reaction and western blot experiments, respectively. Synaptic plasticity was evaluated by the immunolocalization of synaptophysin (Syn). Exposure of the hippocampal neurons to high glucose (75 mM for 72 h) resulted in cell apoptosis, decreased mRNA and protein expression levels of three synaptic plasticity?related proteins (Syn, Arc and cyclic AMP response element?binding protein), and changes in the cellular distribution of Syn, indicating loss of synaptic density. These effects of high glucose were partially or completely reversed by prior administration of BDNF (50 ng/ml for 24 h). Pre?treatment with wortmannin, a phosphatidylinositol?3?kinase (PI3K) inhibitor, suppressed the ability of BDNF to inhibit the effects of high glucose. In addition, BDNF significantly upregulated the tropomyosin?related kinase B, its cognate receptor, Akt and phosphorylated Akt at the protein levels under high glucose conditions. In conclusion, high glucose induced apoptosis and downregulated synaptic plasticity?related proteins in hippocampal neurons. These effects were reversed by BDNF via the PI3K/Akt signaling pathway.

SUBMITTER: Zhong Y

PROVIDER: S-EPMC6257855 | biostudies-other | 2019 Jan

REPOSITORIES: biostudies-other

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Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway.

Zhong Yuan Y Zhu Yitong Y He Ting T Li Wei W Li Qinjie Q Miao Ya Y

International journal of molecular medicine 20181015 1

It is not known whether brain‑derived neurotrophic factor (BDNF) protects hippocampal neurons from high glucose‑induced apoptosis and/or synaptic plasticity dysfunction. The present study aimed to assess whether BDNF exerted a neuroprotective effect in rat hippocampal neurons exposed to high glucose and examine the underlying mechanisms. The apoptosis of primary hippocampal neurons was assessed by Annexin V‑fluorescein isothiocyanate/propidium iodide staining. The mRNA and protein expression lev ...[more]

PMID: 30365051

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Project description:BackgroundHippocampal CA1 pyramidal neurons receive two excitatory glutamatergic synaptic inputs: their most distal dendritic regions in the stratum lacunosum-moleculare (SLM) are innervated by the perforant path (PP), originating from layer III of the entorhinal cortex, while their more proximal regions of the apical dendrites in the stratum radiatum (SR) are innervated by the Schaffer-collaterals (SC), originating from hippocampal CA3 neurons. Endocannabinoids (eCBs) are naturally occurring mediators capable of modulating both GABAergic and glutamatergic synaptic transmission and plasticity via the CB1 receptor. Previous work on eCB modulation of excitatory synapses in the CA1 region largely focuses on the SC pathway. However, little information is available on whether and how eCBs modulate glutamatergic synaptic transmission and plasticity at PP synapses.Methodology/principal findingsBy employing somatic and dendritic patch-clamp recordings, Ca(2+) uncaging, and immunostaining, we demonstrate that there are significant differences in low-frequency stimulation (LFS)- or DHPG-, an agonist of group I metabotropic glutamate receptors (mGluRs), induced long-term depression (LTD) of excitatory synaptic transmission between SC and PP synapses in the same pyramidal neurons. These differences are eliminated by pharmacological inhibition with selective CB1 receptor antagonists or genetic deletion of the CB1 receptor, indicating that these differences likely result from differential modulation via a CB1 receptor-dependent mechanism. We also revealed that depolarization-induced suppression of excitation (DSE), a form of short-term synaptic plasticity, and photolysis of caged Ca(2+)-induced suppression of Excitatory postsynaptic currents (EPSCs) were less at the PP than that at the SC. In addition, application of WIN55212 (WIN) induced a more pronounced inhibition of EPSCs at the SC when compared to that at the PP.Conclusions/significanceOur results suggest that CB1 dependent LTD and DSE are differentially expressed at the PP versus SC synapses in the same neurons, which may have an impact on synaptic scaling, integration and plasticity of hippocampal CA1 pyramidal neurons.

Dataset Information

Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway.

Publications

Brain-derived neurotrophic factor inhibits hyperglycemia-induced apoptosis and downregulation of synaptic plasticity-related proteins in hippocampal neurons via the PI3K/Akt pathway.

Similar Datasets

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