Abstract
SummarySynapse loss is a key feature of dementia, but it is unclear whether synaptic dysfunction precedes degenerative phases of the disease. Here, we show that even before any decrease in synapse density, there is abnormal turnover of cortical axonal boutons and dendritic spines in a mouse model of tauopathy-associated dementia. Strikingly, tauopathy drives a mismatch in synapse turnover; postsynaptic spines turn over more rapidly, whereas presynaptic boutons are stabilized. This imbalance between pre- and post-synaptic stability coincides with reduced synaptically driven neuronal activity in pre-degenerative stages of the disease.
Highlights
A major hallmark of neurodegenerative dementia is the loss of neuronal synapses
The rTg4510 transgenic mouse line, in which the P301L-mutated human tau (MAPT) gene that causes Frontotemporal Dementia with Parkinsonism-17 is expressed in excitatory neurons of the forebrain, recapitulates many characteristics of neurodegenerative disease (Ramsden et al, 2005; Santacruz et al, 2005)
Pursuing the hypothesis that synaptic dysfunction is an early harbinger of dementia, we have determined when and how changes in synapse number are first manifested in rTg4510 mice
Summary
A major hallmark of neurodegenerative dementia is the loss of neuronal synapses. Deposition of insoluble neurofibrillary tangles, the hallmark of tauopathy-related dementia, begins in the cortex from 5 months of age (Ramsden et al, 2005; Spires et al, 2006). This is followed by age-dependent loss of cortical neurons and progressive forebrain atrophy (Ramsden et al, 2005; Spires et al, 2006). Pursuing the hypothesis that synaptic dysfunction is an early harbinger of dementia, we have determined when and how changes in synapse number are first manifested in rTg4510 mice
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