Abstract
In addition to the core clinical features of fluctuating cognition, visual hallucinations, and parkinsonism, individuals with dementia with Lewy bodies (DLB) frequently experience chronic and debilitating major depression. Treatment of depression in DLB is hampered by a lack of available effective therapies and standard serotonergic medication for major depressive disorder (MDD) is typically ineffective. Dysfunction of dopaminergic neurotransmission contributing to anhedonia and loss of motivation has been described in MDD. The subgenual anterior cingulate cortex (sgACC) is important in mood regulation and in the symptomatic expression of depression, displaying structural, functional and metabolic abnormalities in MDD. To assess dopaminergic and serotonergic synaptic changes in DLB, post mortem sgACC tissue from DLB donors with and without depression was investigated using high-resolution stimulated emission depletion (STED) microscopy, as well as Western and dot blotting techniques. STED imaging demonstrated the presence of α-synuclein within individual dopaminergic terminals in the sgACC, α-synuclein presence showing a significant positive correlation with increased synaptosomal associated protein 25 kDa (SNAP25) volumes in depressed DLB cases. A reduction in dopaminergic innervation in the sgACC was observed in DLB cases with depression compared to controls (p < 0.001), but not in non-depressed DLB donors, along with reduced levels of multiple dopaminergic markers and receptors. Limited alterations were observed in serotonergic markers. Our work demonstrates a role for dopaminergic neurotransmission in the aetiology of depression in DLB. Careful and selective targeting of dopaminergic systems in the sgACC may be a therapeutic option for treatment of depression in DLB.