Impaired Short-Term Plasticity in Mossy Fiber Synapses Caused by Mitochondrial Dysfunction of Dentate Granule Cells Is the Earliest Synaptic Deficit in a Mouse Model of Alzheimer's Disease

  • Lee S
  • Kim K
  • Ryu S
  • et al.
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Abstract

Alzheimer's disease (AD) in the early stages is characterized by memory impairment, which may be attributable to synaptic dysfunction. Oxidative stress, mitochondrial dysfunction, and Ca 2+ dysregulation are key factors in the pathogenesis of AD, but the causal relationship between these factors and synaptic dysfunction is not clearly understood.Wefound that in the hippocampus of an AD mouse model (Tg2576), mitochondrial Ca 2+ handling in dentate granule cells was impaired as early as the second postnatal month, and this Ca 2+ dysregulation caused an impairment of post-tetanic potentiation in mossy fiber-CA3 synapses. The alteration of cellular Ca 2+ clearance in Tg2576 mice is region-specific within hippocampus because in another region, CA1 pyramidal neuron, no significant difference in Ca 2+ clearance was detected between wild-type and Tg2576 mice at this early stage. Impairment of mitochondrial Ca 2+ uptake was associated with increased mitochondrial reactive oxygen species and depolarization of mitochondrial membrane potential. Mitochondrial dysfunctions in dentate granule cells and impairment of post-tetanic potentiation in mossy fiber-CA3 synapses were fully restored when brain slices obtained from Tg2576 were pretreated with antioxidant, suggesting that mitochondrial oxidative stress initiates other dysfunctions. Reversibility of early dysfunctions by antioxidants at the preclinical stage of AD highlights the importance of early diagnosis and antioxidant therapy to delay or prevent the disease processes. ©2012 the authors.

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Lee, S. H., Kim, K.-R., Ryu, S.-Y., Son, S., Hong, H. S., Mook-Jung, I., … Ho, W.-K. (2012). Impaired Short-Term Plasticity in Mossy Fiber Synapses Caused by Mitochondrial Dysfunction of Dentate Granule Cells Is the Earliest Synaptic Deficit in a Mouse Model of Alzheimer’s Disease. Journal of Neuroscience, 32(17), 5953–5963. https://doi.org/10.1523/JNEUROSCI.0465-12.2012

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