Seeding and transgenic overexpression of alpha‐synuclein triggers dendritic spine pathology in the neocortex

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.

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…Blumenstock et al. () reported that α‐synuclein accumulation induced by intrastriatal injection of PFFs caused dendritic spine loss in the mouse somatosensory cortex.…”

“…For example, Nouraei et al (2018) injected PFFs into mice hippocampus and caused formation of α-synuclein-positive inclusions, which were insufficient to cause hippocampal cell death, but their expansion was negatively correlated with memory capacity. Blumenstock et al (2017) reported that α-synuclein accumulation induced by intrastriatal injection of PFFs caused dendritic spine loss in the mouse somatosensory cortex.…”

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

“…These presynaptic aggregates correspond to reduced dendritic spine density, suggesting that they impact synaptic function. Dendritic spine density is also reduced in rodent models of α‐syn aggregation . Indeed, fibril‐induced formation of α‐syn aggregates causes major reduction in mushroom spine density at a time point preceding neuronal death .…”

“…Dendritic spine density is also reduced in rodent models of α-syn aggregation. 154 Indeed, fibril-induced formation of α-syn aggregates causes major reduction in mushroom spine density at a time point preceding neuronal death. 11 Exposure of neurons from α-syn knockout mice to fibrils does not affect spine density, demonstrating that corruption of endogenous α-syn causes synaptic structural defects.…”

Pathological α-synuclein triggers synaptic NMDA receptor dysfunction through altered trafficking

“…Moreover, dendritic spine loss and compromised neuronal and network activities have been observed before neuronal death after exposure to extracellular α-syn (e.g. PFFs) or in α-syn transgenic mice (e.g., A53T and WT-α-syn overexpression) [10,12,49,50,[58][59][60]. However, the mechanism through which α-syn abnormalities affect synaptic transmission remains unclear.…”