title: Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors.
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.
authors.affiliation: Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, Lund, Sweden. helene.hall@med.lu.se
authors.forename: Hélène
authors.initials: H
authors.lastname: Hall
authors.forename: Michael
authors.initials: M
authors.lastname: Jewett
authors.forename: Natalie
authors.initials: N
authors.lastname: Landeck
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nilsson
authors.forename: Ulrika
authors.initials: U
authors.lastname: Schagerlöf
authors.forename: Giampiero
authors.initials: G
authors.lastname: Leanza
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
mesh_terms: D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D000229:Dependovirus / Q000235:genetics*; D020667:Diagonal Band of Broca / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008570:Memory, Short-Term / Q000187:drug effects; D008822:Mice, Transgenic; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011995:Recombination, Genetic / Q000235:genetics; D020665:Septum of Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019076:Transgenes; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D004298:Dopamine