Abstract
The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.
Highlights
One form of impulsivity refers to the difficulty in inhibiting incorrect or inappropriate responses – motor (Evenden 1999; Robbins 2002) or waiting impulsivity (Robinson et al 2009) – which can be assessed in rodents with the 5-choice serial reaction time task (5-CSRTT) (Carli et al 1983; Oliver et al 2009; Robbins 2002; Walker et al 2011)
In order to investigate a potential relationship between alpha-synuclein and impulsivity, we evaluated motor impulsivity in strains of mice that differ in the expression of alpha-synuclein
Mmrn1 has not been shown to be expressed in the brain (Specht & Schoepfer 2004), and is unlikely to contribute to the behavioural phenotype of C57BL/6JOlaHsd mice, in order to ensure that the differences in impulsivity were related to snca, and not adjacent genes affected by the chromosomal deletion, a second experiment was carried out in which wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT
Summary
Mmrn has not been shown to be expressed in the brain (Specht & Schoepfer 2004), and is unlikely to contribute to the behavioural phenotype of C57BL/6JOlaHsd mice, in order to ensure that the differences in impulsivity were related to snca, and not adjacent genes affected by the chromosomal deletion, a second experiment was carried out in which wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. We correlated levels of snca expression with impulsivity in a panel of BXD recombinant inbred mouse strains (Chesler et al 2003)
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