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

Department of Neuroscience, Retzius väg 8:A3-417, Karolinska Institutet, S-17177 Stockholm, Sweden.
European Journal of Neuroscience (Impact Factor: 3.18). 05/2006; 23(8):2035-47. DOI: 10.1111/j.1460-9568.2006.04733.x
Source: PubMed


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.

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Available from: Misha Zilberter
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    • "Indeed, behavioral tests would not be relevant for such context as the signs of cognitive impairments for this AD model have not been observed before 10 months of age (Minkeviciene et al. 2008). However, we have previously reported significant progressive impairment in spike timing-dependent plasticity in the very same TG mice that were several months younger (Shemer et al. 2006). In this study, we show that the acute Ab 1-42 application strongly reduces the tetanus stimulationinduced LTP, while this toxic effect is completely prevented by the presence of OES. "
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    • "In the present study, APP/PS1 double transgenic mice overexpressing chimeric mouse/human APP with the Swedish double mutation (K595N and M596L) and human PS1-ΔE9 (deletion of presenilin 1 exon 9) mutation were used [3] [4]. This line is originally maintained in a hybrid C3HeJ C57BL6/ J F1 background and manifests a rapid accumulation of amyloid plaques in the cortex and hippocampus beginning at about 3 months of age [4] [5] [6] [7]. Additionally, these mice exhibit other pathological featured alterations associated with AD [8] [9]. "
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    • "In addition, select sections were stained for the N-terminal human Aβ-specific antibody W02 (Genetics, Switzerland) to visualize diffuse amyloid deposits . Amyloid plaques were examined in septal hippocampal sections using an Olympus microscope at ×10–20 magnification to verify that transgenic animals were expressing amyloid pathology, as described previously (Shemer et al. 2006). Consistent with earlier studies (Garcia-Alloza et al. 2006; Minkeviciene et al. 2009), amyloid plaques only started to build up in 5-month-old APdE9 mice (corresponding to ∼0.1% amyloid plaque load at this age, whereas amyloid load can exceed 20% of the cortical volume in aged APP/PS1 mice). "
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