Non‐fibrillar β‐amyloid abates spike‐timing‐dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors
Copyright policy )Non‐fibrillar β‐amyloid abates spike‐timing‐dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors
AbstractCognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid β protein oligomers (Aβols) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian‐related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age‐dependent Aβ accumulation affects the induction of spike‐timing‐dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Aβ pathology and was virtually absent in mice with advanced Aβ burden. A decreased α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA)/N‐methyl‐d‐aspartate (NMDA) receptor‐mediated current ratio implicated postsynaptic mechanisms underlying Aβ synaptotoxicity. The integral role of Aβols in these processes was verified by showing that pretreatment of cortical slices with Aβ(25−35)ols disrupted spike‐timing‐dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor‐mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Aβols perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Aβ pathology. We propose that soluble Aβols trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.
- Vrije Universiteit Amsterdam Netherlands
- Amsterdam UMC Netherlands
- Karolinska Institute Sweden
- University of Szeged Hungary
- Magyar Tudományos Akadémia Könyvtára (Library of the Hungarian Academy of Sciences) Hungary
Male, Time Factors, N-Methylaspartate, Patch-Clamp Techniques, Patch-Clamp Techniques/methods, Action Potentials, Gene Expression, Messenger/metabolism, Mice, Transgenic, Neocortex, Action Potentials/drug effects, Transgenic, Neocortex/pathology, Amyloid beta-Protein Precursor, Mice, SDG 3 - Good Health and Well-being, Alzheimer Disease, Immunohistochemistry/methods, Receptors, Excitatory Amino Acid Agonists, Animals, N-Methylaspartate/pharmacology, Pyramidal Cells/drug effects, AMPA/classification, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology, Amyloid beta-Protein Precursor/genetics, Electric Stimulation/methods, Excitatory Postsynaptic Potentials/drug effects, Synapses/drug effects, Amyloid beta-Peptides, Animal, RZ Other systems of medicine / orvostudomány egyéb területei, Pyramidal Cells, Age Factors, Excitatory Postsynaptic Potentials, Newborn, Excitatory Amino Acid Agonists/pharmacology, Immunohistochemistry, Electric Stimulation, Disease Models, Animal, Animals, Newborn, Amyloid beta-Peptides/chemistry, Disease Models, RNA, Reverse Transcriptase Polymerase Chain Reaction/methods
Male, Time Factors, N-Methylaspartate, Patch-Clamp Techniques, Patch-Clamp Techniques/methods, Action Potentials, Gene Expression, Messenger/metabolism, Mice, Transgenic, Neocortex, Action Potentials/drug effects, Transgenic, Neocortex/pathology, Amyloid beta-Protein Precursor, Mice, SDG 3 - Good Health and Well-being, Alzheimer Disease, Immunohistochemistry/methods, Receptors, Excitatory Amino Acid Agonists, Animals, N-Methylaspartate/pharmacology, Pyramidal Cells/drug effects, AMPA/classification, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology, Amyloid beta-Protein Precursor/genetics, Electric Stimulation/methods, Excitatory Postsynaptic Potentials/drug effects, Synapses/drug effects, Amyloid beta-Peptides, Animal, RZ Other systems of medicine / orvostudomány egyéb területei, Pyramidal Cells, Age Factors, Excitatory Postsynaptic Potentials, Newborn, Excitatory Amino Acid Agonists/pharmacology, Immunohistochemistry, Electric Stimulation, Disease Models, Animal, Animals, Newborn, Amyloid beta-Peptides/chemistry, Disease Models, RNA, Reverse Transcriptase Polymerase Chain Reaction/methods
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