Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors

PLoS One. 2013 May 21;8(5):e64844. doi: 10.1371/journal.pone.0064844. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Choline O-Acetyltransferase / metabolism
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology*
  • Dependovirus / genetics*
  • Diagonal Band of Broca / drug effects
  • Diagonal Band of Broca / metabolism
  • Diagonal Band of Broca / pathology
  • Diagonal Band of Broca / physiopathology
  • Dopamine / pharmacology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Female
  • Gene Expression
  • Genetic Vectors / genetics*
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Memory, Short-Term / drug effects
  • Mice, Transgenic
  • Microdialysis
  • Motor Activity / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Recombination, Genetic / genetics
  • Septum of Brain / metabolism*
  • Septum of Brain / pathology
  • Septum of Brain / physiopathology
  • Transgenes
  • Tyrosine 3-Monooxygenase / metabolism
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism*
  • Ventral Tegmental Area / pathology
  • Ventral Tegmental Area / physiopathology
  • alpha-Synuclein / genetics*

Substances

  • SNCA protein, human
  • alpha-Synuclein
  • Green Fluorescent Proteins
  • Tyrosine 3-Monooxygenase
  • Choline O-Acetyltransferase
  • Dopamine

Grants and funding

This study was supported by grants from the European Research Council (TreatPD 242932), the Swedish Research Council (2008–3092, 2009–2318) and the Swedish Foundation for Strategic Research (Parkinson's models for translational research). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.