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Validating Gpr88 as a new therapeutic target in models of the neuropsychiatric symptoms of Parkinson's Disease

Abstract : Beyond the motor impairment, Parkinson’s disease (PD) is also characterised by an early appearance of psychiatric symptoms such as apathy, depression and cognitive deficits. While current treatments may provide some level of symptomatic relief, their efficacy decreases with time and is limited by the frequent development of adverse effects such as dyskinesia and impulse-control disorders. In this context, we evaluated the orphan receptor Gpr88 as a new therapeutic target. GPR88 is associated with neuropsychiatric disorders, and is highly expressed in the striatum where it exerts inhibitory control over the dopaminergic inputs that degenerate in PD. In rat models of the motor or psychiatric symptoms of PD, we thus knocked-down (KD) the expression of the Gpr88 in different striatal regions, and assessed the effects at behavioural and molecular levels. These models allowed us to reproduce alterations in striatal activity that have been observed in patients, and to demonstrate that localised Gpr88-KD reverses the deficits in motor activity, mood, motivation and cognition, notably through modulation of transcription factor ∆FosB. This work thus supports the relevance of Gpr88 as a therapeutic target for the treatment of PD, as well as for other neuropsychiatric disorders.
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  • HAL Id : tel-02946058, version 1

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Benjamin Galet. Validating Gpr88 as a new therapeutic target in models of the neuropsychiatric symptoms of Parkinson's Disease. Neurobiology. Sorbonne Université, 2018. English. ⟨NNT : 2018SORUS524⟩. ⟨tel-02946058⟩

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