motional memory impairments induced by AAV-mediated verexpression of human-synuclein in dopaminergic neurons of the entral tegmental area

Parkinson’s disease (PD) is associated with extensive degeneration of dopaminergic neurons originating in the substantia nigra pars compacta, but neuronal loss is also found in the ventral tegmental area (VTA). The VTA projects to areas involved in cognitive and emotional processes, including hippocampus, amygdala, nucleus accumbens and prefrontal cortex, and has thus been proposed to play a role in emotional memory impairments in PD. Since the formation of -synuclein inclusions throughout the central nervous system is a pathological hallmark of PD, we studied the progressive effects of synuclein overexpression in the VTA on motor functions, emotional behaviour and emotional memory. Adeno-associated viral (AAV) vectors encoding either human -synuclein or green fluorescent protein (GFP) were injected stereotactically into the VTA, and behaviour was monitored 3 and 8 weeks following AAV injection. At week 8, there was a 22% reduction of TH+ neurons in the VTA. We demonstrate that -synuclein overexpression in dopaminergic neurons of the VTA induced mild motor deficits that appeared 3 weeks following AAV-synuclein injection and were aggravated at week 8. No depressiveor anxiety-like behaviours were found. To address emotional memory, we used the passive avoidance test, a one-trial associative learning paradigm based on contextual conditioning which requires minimal training. Interestingly, emotional memory impairments were found in -synuclein overexpressing animals at week 8. These findings indicate that -synuclein overexpression induces progressive memory impairments likely caused by a loss of function of mesolimbic dopaminergic projections. © 2015 Published by Elsevier B.V. Parkinson’s disease (PD) is a movement disorder characterized y the accumulation of -synuclein-enriched Lewy bodies and loss Abbreviations: AAV, adeno-associated virus; GFP, green fluorescent protein; PD, arkinson’s disease; SN, substantia nigra; TH, tyrosine hydroxylase; VTA, ventral egmental area; WT, wild-type. ∗ Corresponding authors at: Translational Neuropharmacology, Center for Moleclar Medicine, L8:01, Karolinska University Hospital Solna, SE-171 76 Stockholm, weden. Fax: +46 8 517 746 14. E-mail addresses: alexandra.alvarsson@ki.se (A. Alvarsson), er.svenningsson@ki.se (P. Svenningsson). ttp://dx.doi. org/10.1016/j.bbr. 2015.08. 034 166-4328/© 2015 Published by Elsevier B.V. of dopaminergic neurons originating in the substantia nigra (SN) pars compacta projecting to the striatum [1]. However, neurodegeneration in PD is not restricted to SN, but also affects the ventral tegmental area (VTA) where -synuclein aggregates are found also in early stages of the disease [1]. The VTA projects to several brain regions involved in emotional and cognitive processes, including hippocampus [2], nucleus accumbens, amygdala and prefrontal cortex [3]. Although neurons of the VTA are less prone to degenerate in PD compared with neurons of the SN [4], pathological lesions of the mesohippocampal and mesocortical projections have been implicated in the emotional and cognitive symptoms of PD [5,6]. 1 l Brain Research 296 (2016) 129–133