Local cortical overexpression of human wild-type alpha-synuclein leads to increased dendritic spine density in mouse

•Lewy body dementias are defined by cortical alpha-synuclein.•It is unclear how alpha-synuclein affects cortical cells.•Local overexpression of alpha-synuclein leads to increased spine density after 10 weeks.•These findings may have important implications for modeling early stages of cortical dysfunction. Lewy body dementias are characterized by deposition of alpha-synuclein (α-syn) protein aggregates known as Lewy bodies and Lewy neurites in cortical regions, in addition to brainstem. These aggregates are thought to cause the death of dopaminergic neurons in the substantia nigra and other vulnerable cell types in patients, leading to parkinsonism. There is evidence from mice that localized overexpression of wild-type α-syn leads to dopaminergic cell death in the substantia nigra. However, it is not known how cortical neurons are affected by α-syn. In this study, we used viral overexpression of α-syn to investigate whether localized overexpression within the cortex affects the density, length, and morphology of dendritic spines, which serve as a measure of synaptic connectivity. An AAV2/6 viral vector coding for wild-type human α-syn was used to target overexpression bilaterally to the medial prefrontal cortex within adult mice. After ten weeks the brain was stained using the Golgi–Cox method. Density of dendritic spines in the injected region was increased in layer V pyramidal neurons compared with animals injected with control virus. Immunohistochemistry in separate animals showed human α-syn expression throughout the region of interest, especially in presynaptic terminals. However, phosphorylated α-syn was seen in a discrete number of cells at the region of highest overexpression, localized mainly to the soma and nucleus. These findings demonstrate that at early timepoints, α-syn overexpression may alter connectivity in the cortex, which may be relevant to early stages of the disease. In addition, these findings contribute to the understanding of α-syn, which when overexpressed in the wildtype, non-aggregated state may promote spine formation. Loss of spines secondary to α-syn in cortex may require higher expression, longer incubation, cellular damage, concomitant dopaminergic dysfunction or other two-hit factors to lead to synaptic degeneration.