Emotional memory impairments induced by AAV-mediated overexpression of human α-synuclein in dopaminergic neurons of the ventral 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 α-synuclein inclusions throughout the central nervous system is a pathological hallmark of PD, we studied the progressive effects of α-synuclein overexpression in the VTA on motor functions, emotional behaviour and emotional memory. Adeno-associated viral (AAV) vectors encoding either human α-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 α-synuclein overexpression in dopaminergic neurons of the VTA induced mild motor deficits that appeared 3 weeks following AAV-α-synuclein injection and were aggravated at week 8. No depressive- or 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 α-synuclein overexpressing animals at week 8. These findings indicate that α-synuclein overexpression induces progressive memory impairments likely caused by a loss of function of mesolimbic dopaminergic projections.
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm 17176, Sweden. Electronic address: alexandra.alvarsson@ki.se.
A
A
Alvarsson
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm 17176, Sweden.
D
D
Caudal
Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden.
A
A
Björklund
Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, Stockholm 17176, Sweden. Electronic address: per.svenningsson@ki.se.
P
P
Svenningsson
D000818:Animals; D001245:Association Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D000229:Dependovirus; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004644:Emotions / Q000502:physiology*; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D008569:Memory Disorders / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017557:Ventral Tegmental Area / Q000378:metabolism*; D051844:alpha-Synuclein / Q000008:administration & dosage / Q000378:metabolism*
C497604:SNCA protein, human; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins
Adeno-associated viral vectors; Cognition; Memory; Passive avoidance; Ventral tegmental area; α-Synuclein