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Conséquences fonctionnelles, comportementales et adaptatives d'une mutation de la MAO (MonoAmine Oxydase) chez le poisson cavernicole aveugle Astyanax mexicanus.

Abstract : The neurotransmitter serotonin controls a great variety of physiological and behavioral processes. In humans, mutations affecting the monoamine oxidase or MAO, the serotonin-degrading enzyme, are highly deleterious. Yet, blind cavefish of the species A. mexicanus carry a partial loss-of-function mutation in MAO (P106L) and seem to thrive in their subterranean environ-ment. This thesis describes the effects of this mutation, from the molecular level to the population level, in order to decipher the exact contribution of mao P106L in the evolution of cavefish neuro-behavioral traits, during their adaptation to the cave environment.In a first paper, we established 4 fish lines, corresponding to the blind cave-dwelling and the sighted river-dwelling morphs of this species, with or without the mutation. We found that mao P106L strongly affected anxiety-like behaviors. Cortisol measurements showed lower basal levels and an increased amplitude of stress response after a change of environment in fish carrying the mutation. Finally, we studied the distribution of the P106L mao allele in wild populations of cave and river A. mexicanus, and discovered that the mutant allele was present – and sometimes fixed - in all populations inhabiting caves of the Sierra de El Abra. The possibility that this partial loss-of-function mao allele evolves under a selective or a genetic drift regime in the particular cave environment is discussed.In a second paper, we assessed the structural and biochemical consequences of the mutation. We found that the reduction of enzymatic activity of mutant MAO is probably caused by a decrease of flexibility in one of the three loops forming the entrance of the active site, thus reducing the access of substrates. HPLC measurements in brains of mutant and non-mutant larvae and adult fish showed major disturbances in serotonin, dopamine and noradrenalin (and metabolites) contents, demonstrating that the P106L mao mutation is fully responsible for monoaminergic disequilibrium in the cavefish brain. We also discovered that the effects of the mutation were partially compensated by a decrease in activity of the TPH, the serotonin biosynthesis rate-limiting enzyme. Our results shade light on the specificities of fish monoaminergic systems.Finally in order to aggravate the MAO inhibition, we generated the first fish knockout MAO mutant. The KO homozygous mutants were stunted and died during the first weeks of development. Contrary to the dopaminergic system which seemed normal in the KO homozygous mutants, the serotonergic system was strongly impaired; no serotonin positive neuron was detected in the hypothalamus.
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Constance Pierre. Conséquences fonctionnelles, comportementales et adaptatives d'une mutation de la MAO (MonoAmine Oxydase) chez le poisson cavernicole aveugle Astyanax mexicanus.. Neurosciences. Université Paris-Saclay, 2020. Français. ⟨NNT : 2020UPASS084⟩. ⟨tel-02900927⟩

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