The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease

Project Information

HT4PD

Grant agreement ID: 894207

DOI

10.3030/894207

Project closed

EC signature date 20 March 2020

Start date 1 January 2021

End date 31 December 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 295 061,76

EU contribution

€ 295 061,76

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - HT4PD (The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease)

Reporting period: 2021-01-01 to 2023-12-31

Summary of the context and overall objectives of the project

Parkinson’s Disease (PD) is the second most common, progressive, adult onset, neurodegenerative disease in Europe and is characterized by the loss of midbrain dopaminergic neurons and the formation of Lewy bodies in the remaining dopaminergic neurons, causing motor impairment such as bradykinesia, rigidity and slow movement. Dopamine (DA) via L-Dopa therapy ameliorates many but not all symptoms and induces uncontrollable L-Dopa induced dyskinesia (LID), a complicated and debilitating side effect that affects almost all patients following 5-10 years of chronic treatment. L-Dopa induced dyskinesia (LID) affects up to 90% of patients treated with L-DOPA and currently no treatment to ameliorate symptoms exist. There is an urgent need to better understand the pathophysiology underlying this important treatment side effect and to develop drugs to reduce symptoms.

It is known that the neurotransmitters systems of Dopamine and Serotonin interact with each other and it is known that neurons producing serotonin can also metabolize and release L-DOPA which Is thought to contribute to the L-DOPA induced dyskinesia.

We study specific serotonin receptors to better understand this functional interaction and to identify targets for pharmacotherapy aiming to alleviate the dyskinesia. We want to determine the expression pattern of serotonin receptors on a cellular level, determine how modulation thereof alters responses to the drug L-DOPA and to LID in a mouse model of Parkinson.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We are in the process of studying the role a serotonin receptor in the context of L-DOPA induced dyskinesia and have shown that modulating receptor activity also impacts on the severity of L-DOPA induced dyskinesia.
We are currently investigating the molecular underpinnings of this functional interaction in a cell–specific context.

We have shown that pharmacological activation of 5-HT4 receptor activity reduces L-DOPA induced dyskinesia in a mouse model of Parkinson's disease. We further found that this activation does not impact negatively on the anti-akinetic effect of L-DOPA.
Using the RNAscope technology and qPCR, we show that the 5-HT4 receptor in the dorsal striatum is predominantly expressed in D2-receptor expressing medium spiny neurons (MSNs) and that its expression is enhanced in response to Dopamine depletion and L-DOPA treatment.
We therefore conclude that the anti-LID action of 5-HT4R agonssim is mediated via the D2-MSNs.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This is the final report for the grant, but we plan to further investigate the role of this receptor in LID.

RNAscope for 6-OHDA lesioned striatum