Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors.
Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) 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 Abeta 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 Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s 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 Abeta(ol)s 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 Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.
Shemer
Isaac
I
Department of Neuroscience, Retzius väg 8:A3-417, Karolinska Institutet, S-17177 Stockholm, Sweden.
Holmgren
Carl
C
Min
Rogier
R
Fülöp
Livia
L
Zilberter
Misha
M
Sousa
Kyle M
KM
Farkas
Tamás
T
Härtig
Wolfgang
W
Penke
Botond
B
Burnashev
Nail
N
Tanila
Heikki
H
Zilberter
Yuri
Y
Harkany
Tibor
T
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D019579:Neocortex / Q000473:pathology*; D018408:Patch-Clamp Techniques / Q000379:methods; D017966:Pyramidal Cells / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D018091:Receptors, AMPA / Q000145:classification / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013569:Synapses / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018690:Excitatory Amino Acid Agonists; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid