Job ID: 87117

PhD project: Role of 5-HT4 receptors in the modulation of synaptic plasticity within the dentate gyrus: toward a rejuvenation cure?

Position: Ph.D. Student

Deadline: 25 October 2022

Employment Start Date: 26 October 2022

Contract Length: 36 months

City: Bordeaux

Country: France

Institution: University of Bordeaux

Department:

Description:

Currently, the therapeutic management of depression remains far from optimal. Only one third of patients respond to a first antidepressant (AD) treatment, a response that takes 3 to 4 weeks to develop. A few years ago, it was proposed that a possible strategy to achieve a rapid AD efficacy would be to enhance synaptic transmission in the dentate gyrus (DG), a subregion of the hippocampus. In line with this hypothesis, we have recently shown that an increase in synaptic plasticity within the DG, induced by a long-term potentiation (LTP) of its main excitatory afference, the perforant pathway (PP), resulted in very rapid AD-like effects in rats (2 days after LTP). Almost all chemical ADs share the common property of increasing central serotonergic (5-HT) neurotransmission by indirect mechanisms (inhibition of reuptake or catabolism), which in turn would be responsible for the delay of action due to the presence of 5-HT1A autoreceptors inhibiting 5-HT electrical activity. About ten years ago, we showed that 5-HT4 receptor agonists were able to bypass this feedback loop by directly stimulating 5-HT neuronal firing, through the mobilization of a positive, long-loop feedback originating from the medial prefrontal cortex (mPFC). They were at least as effective as conventional ADs on several biological and behavioral markers characteristic of AD action, but 5 to 7 times faster, i.e., as soon as 3 days after their administration. Given this similarity in speed of action, the question of whether 5-HT4 receptors are able of enhancing synaptic plasticity in the DG arises. Indeed, although they are highly expressed in this structure, their influence in modulating this plasticity remains almost unknown. We will try to determine to what extent they play a role, by using electrophysiological (LTP) and morphological (arborization, dendritic spines) approaches. The study will be conducted in a systematic way, by carrying out (i) specific deletion of 5-HT₄ receptors within the mPFC, (ii) brain 5-HT depletions and (iii) local, intra-DG administrations. Indeed, it will be necessary to dissociate the indirect effects of 5-HT4 receptor agonists, linked to a global increase of central 5-HT activity, from their direct effects on DG neurons. As a corollary, these experiments will allow us to verify the validity of a recent hypothesis, which proposes that 5-HT4 receptors have the power to ‘rejuvenate’ some of the DG neurons. The latter are among the very few neurons in the brain that undergo continuous genesis in adulthood, and they are characterized by an increased propensity for synaptic plasticity during the early phases of this adult neurogenesis.

This project could help to reconcile two theories of depression, which often appear to be antagonistic to each other. Thus, the most widespread theory, called ‘serotoninergic’, could prove compatible with the more recent ‘neuroplastic’ theory, which focuses on rapid AD-type effects. For this, it is precisely necessary to know the role of the 5-HT system, and of 5-HT4 receptors in particular, in the control of neurotransmission in the DG.

Methods:

In vivo electrophysiology (field potentials and action potential population) will be the core of the project. The recordings will allow to evaluate the effects of 5-HT4 agents in the modulation of LTPs of different intensities induced in the DG by high frequency stimulations of the PP. Histological studies will then take place on hippocampal sections taken from the stimulated animals, in order to assess (i) the general morphology of the granule neurons (apparent state of maturity), (ii) the characteristics of their dendritic arborization, and (iii) the density and type of dendritic spines they express.

Conditions:

This funded PhD program, for which the internship supervisor is the project leader, was made on the basis of a mixed fundamental research/clinical research call. A team of psychiatrists (Grenoble University Hospital) will conduct a parallel clinical study to determine whether the addition of a 5-HT4 receptor agonist can accelerate the therapeutic efficacy of a conventional antidepressant in depressed patients. Depending on the results obtained, a joint publication of some of the data could be envisaged, in order to reinforce the potential of the manuscript towards high impact journals.

Please send your CV, together with a letter of motivation and two references, to the contact mentioned below.