Thesis defense – Soukaina Es-Safi

Abstract

Current antidepressant drugs (ADs) display limited efficacy and typically require a latency of three to six weeks before clinical improvement is observed. It has been demonstrated that increasing synaptic plasticity within the dentate gyrus (DG) of the hippocampus can induce a rapid and robust antidepressant effect. In this context, serotonin type 4 receptor (5-HT4R) agonists have emerged as promising candidates for the development of fast-acting antidepressants. The aim of this thesis was to investigate the role of 5-HT4Rs in modulating hippocampal synaptic plasticity within the DG. However, 5-HT4R agonists are known to enhance central serotonergic (5-HT) neuronal activity through “long-loop feedback” originating from the medial prefrontal cortex (mPFC), thereby indirectly stimulating other 5-HT receptor subtypes in the hippocampus, including those expressed in the DG. To dissociate the direct effects of 5-HT4R activation within DG neurons from the indirect effects mediated by the mPFC, we first developed a molecular biology tool based on short hairpin RNA (shRNA) expressed by lentiviral vectors (shRNA-LV), allowing for the inhibition of 5-HT4R expression specifically in the mPFC. This tool was validated using in vivo intracerebral microdialysis, which demonstrated that 5-HT4R stimulation no longer induced an increase in hippocampal 5-HT release in animals injected with the shRNA-LV construct. Next, using in vivo extracellular electrophysiology, we examined the effects of the selective 5-HT4R agonist prucalopride on long-term potentiation (LTP) induced in the DG following high-frequency stimulation (HFS) of the perforant path (PP) in anesthetized rats. LTP was assessed by recording field potentials (FPs) and population spikes (PSs) from granule cells in the DG. Our results show that acute prucalopride treatment in naïve rats reduced the LTP success rate for both FPs and PSs compared to controls, without significantly affecting LTP amplitude. In rats injected with shRNA-LV and acutely treated with prucalopride, this reduction was restored to control levels for both FPs and PSs, again without changes in LTP amplitude. Subchronic (three-day) prucalopride treatment in naïve rats once again reduced the LTP success rate for FPs without altering their amplitude. In contrast, the PS success rate remained similar to that observed after acute treatment, but PS amplitude was significantly and markedly decreased. In shRNA-LV–injected rats receiving the same subchronic treatment, the LTP success rate for FPs was restored, and a trend toward increased FP amplitude was observed compared to controls at the end of the recording period. Taken together, these findings support the involvement of 5-HT4Rs in the modulation of synaptic plasticity within the DG. Activation of these receptors in the mPFC impairs LTP induction, an effect that can be reversed by suppressing their expression.

Keywords: Serotonin type 4 receptors, long-term potentiation, rapid-acting antidepressants, medial prefrontal cortex, dentate gyrus, interfering RNA.

Jury

• M. CHAGRAOUI Abdeslam, Université de Rouen, Rapporteur M. MOULEDOUS Lionel, Université de Toulouse, RapporteurM. LUCAS Guillaume, Université de Bordeaux, Directeur de thèse
• M HADDJERI Nasser, Université Claude Bernard Lyon 1,  (membre invité)
• M. GUIARD Bruno, Université de Toulouse, Examinateur
• M. SPAMPINATO Umberto, Université de Bordeaux, Examinateur