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

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.