Guillaume BOUISSET – PhD defense

PhD defense in french

Zoom link : https://univ-tlse3-fr.zoom.us/j/99182743985

Team : REMEMBER

Supervisor : Lauve VERRET (CRCA-CBI)

Committee members :

• Bertrand Lamboblez – rapporteur
• Hélène Marie – rapporteure
• Francesca Sargolini – rapporteure
• Vincent Fourcassié – examinateur
• Laure Verret – directrice de thèse

Abstract :

Alzheimer’s disease (AD) is associated with abnormal brain activity that underlies cognitive deficits. It is now well-established that dysfunction of GABAergic neurons expressing parvalbumin (PV) protein contributes to these alterations in brain activity—and thus to cognitive impairment—in mouse models and AD patients. In the adult brain, PV neurons are frequently associated with a specialized form of extracellular matrix, the perineural net (PNN), the presence of which would contribute to the long-term maintenance of a PV-dependent brain network. We recently demonstrated that the presence of PNN around PV cells is reduced in the hippocampus of the Tg2576 mouse model of AD, and that it could contribute to the memory deficits observed in this model. Furthermore, young adult Tg2576 mice exposed to an enriched environment (EE) show an increase in the number of quantifiable PV/PNN interneurons in the hippocampus, as well as long-lasting cognitive improvement.

In this thesis, we tested the hypothesis that environmental stimulus-induced remodeling of hippocampal PV/PNN interneurons is required for cognitive improvement of Tg2576 mice. To address this question, in a first study we sought to prevent EE-dependent remodeling of PV interneurons and their PNN in hippocampal area CA1 specifically—via a targeted injection of chondroitinase-ABC (ChABC)—and observed that this is sufficient to suppress the beneficial effects of EE on spatial memory performance (CA1-dependent), without affecting social memory improvements (CA2-dependent). This strongly suggests that the beneficial effects of EE on memory performance in AD mouse model is underpinned, at least partially, by an increase in the activity of hippocampal PV neurons and/or the presence of PNN. Furthermore, based on recent studies, we investigated whether exposing Tg2576 mice to visual and/or auditory stimuli at gamma frequency (40Hz) mimics the effects of a stay in EE on PV/PNN remodeling and memory performance. This experiment did not provide conclusive results on the potential effects of multimodal gamma stimulations on PV interneurons. Finally, we used the innovative high-resolution microscopy technique Random Illumination Microscopy (RIM) to determine whether the differences in PNN numbers observed under different experimental conditions (Tg2576 and non-transgenic mice, exposed or not to EE, injected or not by ChABC) are accompanied by remodeling of the presence of perisomatic synapses on hippocampal PV neurons.

Thus, our work identifies PV neurons and their extracellular matrix PNN as key players in the long-term behavioral improvement of AD mice following early environmental stimuli, making them therapeutic targets of interest for fighting cognitive disorders associated with the pathology.