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Hortense Fanet will defend her PhD entitled  "Effect of tetrahydrobiopterin supply in physiological and pathological conditions: from neurobiology to behavior" on thursday, the 20 of december, 2018 at 14h in the amphithéâtre Broca Nouvelle Aquitaine.

Her jury was composed of:

President : François Georges, Université de Bordeaux

Rapporteur : Denis hervé, Université de Paris

Rapporteur : Sylvie Chalon, Université de Tours

Examinator : Caroline Menard, Université Laval

Invited: Pierre Trifilieff

Invited: Fathi Moussa, Université de Paris

Thesis supervisor: Sylvie Vancassel

Thesis supervisor: Frédéric Calon

Abstract

Tetrahydrobiopterin (BH4) is the required cofactor for the activity of the enzymes involved in the synthesis of dopamine, serotonin and nitric oxide. BH4 is therefore necessary for many central and peripheral physiological processes including neurotransmission, inflammatory response, oxidative stress regulation, vascular and endothelial function, and metabolism. However, BH4 is prone to oxidation and degradation, and decreased BH4 brain level has been observed in many neuropsychiatric diseases including Alzheimer's disease and major depression. Consequently, the decrease in BH4 levels in these pathologies could contribute to the onset and aggravation of symptoms. Despite these observations, the effects of BH4 administration on brain function and related physiological and pathological behavior remain largely unexplored.

The aim of this thesis was to characterize the effects of peripheral BH4 administration on brain function and related behaviors. We investigated the effects of BH4 on the mesolimbic dopaminergic system and motivation in physiological condition and during acute inflammation. Then, we explored the therapeutic potential of BH4 in the treatment of Alzheimer's disease.

We first demonstrated that BH4 crossed the blood-brain barrier and that a peripheral injection of BH4 increased its cerebral levels. Under physiological condition, administration of BH4 potentiates dopamine release into the nucleus accumbens and motivated behaviors. In acute LPS-induced neuroinflammation, administration of BH4 reduced neuroinflammation. Therefore, BH4 may have beneficial effects on dopaminergic disorders induced by inflammation. In our second study, we demonstrated that chronic administration of BH4 reversed memory deficits observed in the transgenic triple murine model of Alzheimer's disease. We also observed a decrease in neuroinflammatory marker and an improvement in glucose tolerance. However, these memory, metabolic and inflammatory improvements were not accompanied by a decrease in amyloid and tau pathologies.

This work contributes to a better characterization of the neurobiological and behavioral effects of the BH4 and reinforces its therapeutic potential.