HT4PD SIGNED

Project "HT4PD" data sheet

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 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, 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.