HT4PD · The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-01-01 → 2023-12-31
- EU contribution
- €295,062
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
The role of the serotonin 5-HT4 receptor in motor and non-motor symptoms of Parkinson’s disease
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.
Data: CORDIS, © European Union
Project objective
Parkinson’s Disease (PD) is caused by dopaminergic neuron loss resulting in motor symptoms that are treated with L-DOPA.However, ≤90% of patients develop involuntary movements, termed L-DOPA induced dyskinesia (LID). Another less well studied, buthighly occurring PD symptom is depression.There is evidence that the serotonin system is implicated in both, LID and PD-linked depression. Serotonergic (5-HT) neuronsuncontrollably release L-DOPA-derived dopamine, and HTR1a/b agonists counteract such release and LIDs. Serotonin re-uptakeinhibitors (SSRIs) also attenuate LID, through a still unknown mechanism. The striatally enriched Gαs-coupled receptor, HTR4, has thepotential to enhance excitability of spiny projection neurons, to affect the balance of striatal pathways that is disrupted in PD and is acandidate to modulate LID and PD-depression.D2 agonists reduce depressive behavior in PD models, pointing towards a role for the striatum. Specifically, the dorsolateral striatumshows diminished metabolism, in contrast to non-PD-depression where the ventral striatum is a substrate. HTR4 in cortex andhippocampus was linked to antidepressant action. Agonists and overexpression yield anti-depressant-like responses, however,striatal HTR4 in PD-depression has not been examined.1. We will determine HTR4 protein expression on a cellular level (dSPNs, iSPNs) in transgenic mice. We will virally overexpress,knockdown and pharmacologically manipulate HTR4 and assess striatally-driven behaviors.2. We will probe HTR4 in motor symptoms by altering expression/activity in unilaterally 6-OHDA lesioned mice. We will evaluate LIDonset/severity, dyskinesia markers and LTP, depotentiation and LTD.3. We will test bilaterally-lesioned mice with altered HTR4 expression/activity in depression/anxiety paradigms. We will determinethe effect on the action of D2, HTR1a agonists and SSRIs.Our comprehensive investigation of HTR4 will lead to a new understanding and treatment of PD.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
- View on CORDIS
- DOI: 10.3030/894207
- https://ipnp.paris5.inserm.fr/research/teams-and-projects/23-team-rebholz
Data: CORDIS, © European Union