Project description
Gaining a deeper understanding of PD and more effective treatments
Parkinson’s disease (PD) is caused by dopaminergic neuron loss that leads to motor symptoms currently treated with L-DOPA. Unfortunately, up to 90 % of patients develop involuntary movements, termed L-DOPA induced dyskinesia (LID), often accompanied by PD-associated depression. The serotonin system is implicated in LID and depression in PD patients. The striatally enriched serotonin receptor HTR4 has the potential to enhance the excitability of spiny projection neurons, affecting the balance of striatal pathways that are disrupted in PD. Thus, HTR4 is an obvious candidate for the modulation of LID and depression related to PD. The EU-funded HT4PD project aims to comprehensively investigate the role of HTR4 in the development of PD-associated symptoms using transgenic mice models, leading to a deeper understanding of PD and more effective treatments.
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, but
highly occurring PD symptom is depression.
There is evidence that the serotonin system is implicated in both, LID and PD-linked depression. Serotonergic (5-HT) neurons
uncontrollably release L-DOPA-derived dopamine, and HTR1a/b agonists counteract such release and LIDs. Serotonin re-uptake
inhibitors (SSRIs) also attenuate LID, through a still unknown mechanism. The striatally enriched Gαs-coupled receptor, HTR4, has the
potential to enhance excitability of spiny projection neurons, to affect the balance of striatal pathways that is disrupted in PD and is a
candidate to modulate LID and PD-depression.
D2 agonists reduce depressive behavior in PD models, pointing towards a role for the striatum. Specifically, the dorsolateral striatum
shows diminished metabolism, in contrast to non-PD-depression where the ventral striatum is a substrate. HTR4 in cortex and
hippocampus 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 LID
onset/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 determine
the 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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine neurology parkinson
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2019
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
75654 PARIS
France
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.