Abstract
Although misfolded and aggregated α‐synuclein (α‐syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α‐synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long‐term in vivo imaging of apical dendrites was performed in mice overexpressing wild‐type human α‐synuclein. Additionally, intracranial injection of preformed α‐synuclein fibrils was performed to induce cortical α‐syn pathology. We find that α‐synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age‐dependent manner. We also provide evidence for the detrimental effects of seeded α‐synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology in vivo.
Highlights
The mammalian brain contains a complex network of billions of neurons communicating through different types of synapses that can be severely and irreversibly disturbed by neurodegeneration
Overexpression of wild-type human a-synuclein leads to changes in dendritic spine density and dynamics in aged mice
This study presents converging evidence from two distinct approaches for the adverse effects of a-syn accumulation for the density and structural plasticity of dendritic spines in the cerebral cortex
Summary
The mammalian brain contains a complex network of billions of neurons communicating through different types of synapses that can be severely and irreversibly disturbed by neurodegeneration. In synucleinopathies like Parkinson’s disease (PD) or dementia with Lewy bodies (DLB), progressive neurodegeneration is linked to misfolding and intracellular aggregation of the synaptic protein a-synuclein (a-syn; Clayton & George, 1999; Lucking & Brice, 2000) and leads to motor as well as cognitive deficits and to dementia (Spillantini et al, 1997; Burn, 2004; Aarsland et al, 2008). Cytosolic a-syn inclusions called Lewy bodies (Spillantini et al, 1998) are a prerequisite for the histopathological diagnosis of PD and DLB, only an imperfect correlation between the Lewy body load and severity of cognitive impairment is known (Hughes et al, 1992; Parkkinen et al, 2005). Presynaptic a-syn oligomers and micro-aggregates are thought to be responsible for neurodegeneration as well as for dendritic spine loss observed in postmortem DLB brains (Kramer & Schulz-Schaeffer, 2007)
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