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Adaptations de la cascade de signalisation AMPc/PKA dans le striatum au cours de la maladie de Parkinson et de son traitement par la L-DOPA : étude par imagerie de biosenseurs sur un modèle animal

Abstract : Neuromodulatory signals trigger adaptations in neuronal functions via complex integrative properties. Among the various existing intracellular signaling pathways, the cAMP/PKA cascade plays a critical role in the cellular response to dopamine. To analyze these integrative processes, we combine biosensor imaging in mouse brain slices with in silico modelisation of the intracellular signaling in D1 and D2 medium-sized spiny neurons. In a first part of my thesis work, we analyze the dynamics of cAMP/PKA signaling in striatal neurons stimulated by transient dopaminergic signals, such as those associated with reward. With imaging we show that the dopamine D​2 receptors can sense phasic dopamine signals at the level of cAMP, a thought that has been argued for long. Moreover ​in silico simulations suggest that D2 spiny neurons could sense the interruptions in tonic dopamine levels associated with aversion in the animal. This work was published in (​Yapo et al., ​J Physiol 2017​). In a second part, we analyzed the effect of such brief dopaminergic signals on the nuclear PKA-dependent signaling. In comparison to cortical neurons, we show that the striatal neurons display a positive feedforward mechanism which strengthens the nuclear responses. This peculiar situation, which contrasts with the usual homeostatic feedback mechanisms found in biology, leads to all-or-nothing and extremely sensitive responses. We believe that this mechanism allows for the detection of transient dopaminergic signals. This work was published in (​Yapo et al., ​J Cell Science​ 2018​). Lastly a third part, that will be introduced as preliminary data, consisted in analyzing the adaptations of the striatal neurons following a dopamine depletion, such as the one found in Parkinson’s disease. We observed in our mouse model an hypersensitivity of the D1 spiny neurons to dopamine, already described by other groups. Additionally we show that striatal neurons display an increased phosphodiesterase activity. A better understanding of these pathological adaptations could lead to the emergence of new therapeutic strategies.
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https://tel.archives-ouvertes.fr/tel-02901403
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Submitted on : Friday, July 17, 2020 - 10:38:18 AM
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  • HAL Id : tel-02901403, version 1

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Cédric Yapo. Adaptations de la cascade de signalisation AMPc/PKA dans le striatum au cours de la maladie de Parkinson et de son traitement par la L-DOPA : étude par imagerie de biosenseurs sur un modèle animal. Biologie cellulaire. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS603⟩. ⟨tel-02901403⟩

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