Abstract
Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.
Highlights
Parkinson’s disease (PD) is characterized by the presence of motor symptoms, resulting from the loss of striatal dopamine (DA) following neurodegeneration of dopaminergic cells in the substantia nigra (SN) [1,2,3]
The aim of this study was to assess the effects of combined targeted overexpression of human wild-type a-syn in the ventral tegmental area (VTA) and MS/vDBB in rats using rAAV5 vectors
Both dopaminergic neurons in the VTA and cholinergic neurons in the MS/vDBB were efficiently transduced by this serotype of AAV vector
Summary
Parkinson’s disease (PD) is characterized by the presence of motor symptoms, resulting from the loss of striatal dopamine (DA) following neurodegeneration of dopaminergic cells in the substantia nigra (SN) [1,2,3]. The clinical expression of the disease is more heterogeneous as patients suffer from a variety of additional non-motor symptoms, including sleep disturbances, olfactory deficits, cognitive impairment, neuropsychiatric disorders, and autonomic dysfunction [4,5]. The cognitive deficit seen in PD causes disturbances in both executive functions and memory [6] and may lead to dementia in 30 to 40% of the patients as the disease progresses [7,8]. Non-dopaminergic cell groups appear to be affected, including those in the cholinergic, serotonergic and noradrenergic systems [see [10] for an extensive review]. The alteration of the cholinergic system is more severe in cognitively impaired PD patients [13] as well as in demented PD patients [14]
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