Our team study dopaminergic and serotonergic signaling in the brain in health and disease states. In particular, focusing on Parkinson’s disease (PD) and major depressive disorder, as well as their link through common molecular mechanisms and underlying neuronal circuits.
Parkinson’s Disease (PD) is the second most common, progressive neurodegenerative disease, with a prevalence of up to 4% in the aged population for which no cure is available. Degeneration of dopamine producing neurons causes a lack of dopamine in the brain, which is characterized by motor impairment. Substitution of dopamine (DA) via L-DOPA is the gold standard therapy. It ameliorates the symptoms but induces L-DOPA induced dyskinesia (LID), a debilitating side effect that occurs in almost all patients following several years of treatment. Non-motor symptoms of PD, such as depression or anxiety, are highly co-morbid, but have only in recent years come to the forefront of research. For example, up to 50% of PD patients are clinically depressive, but treatment is far from successful since it is also evident that the affected brain regions are not the identical to those affected in depression that is not related to PD. There is evidence that the serotonin system is implicated in both, LID and PD-linked depression.
The aim of the team is to understand how the serotonin and the dopamine systems interact, in particular which of the 14 existing serotonin receptors plays a role in PD and LID.
Understanding the molecular mechanisms will enable the development of effective, more specific and less side effect-producing therapies for PD.
A second line of research is to further define the role of the kinase CK2 in the brain, especially in dopaminergic and serotonergic function. We have found that reducing expression of CK2 in the prefrontal cortex leads to an anti-depressed like phenotype in mice. We will determine the mechanism by which this is achieved, focusing on a positive feedback loop involving the prefrontal cortex, Raphe Nuclei and hippocampus and using a variety molecular, pharmacological, behavioral and electrophysiological tools.
Castello J, Cortés M, Malave L, Kottmann A, Sibley DR, Friedman E, Rebholz H. The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia. Sci Rep. 2020 Feb 13;10(1):2542. doi: 10.1038/s41598-020-59011-5. PubMed PMID: 32054879; PubMed Central PMCID: PMC7018760.
Castello J, LeFrancois B, Flajolet M, Greengard P, Friedman E, Rebholz H. CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior. Mol Psychiatry. 2018 Apr;23(4):872-882. doi: 10.1038/mp.2017.240. Epub 2017 Nov 21. PubMed PMID: 29158580.
Cortés M, Malave L, Castello J, Flajolet M, Cenci MA, Friedman E, Rebholz H. CK2 Oppositely Modulates l-DOPA-Induced Dyskinesia via Striatal Projection Neurons Expressing D1 or D2 Receptors. J Neurosci. 2017 Dec 6;37(49):11930-11946. doi: 10.1523/JNEUROSCI.0443-17.2017. Epub 2017 Nov 2. PubMed PMID: 29097596; PubMed Central PMCID: PMC6596830.
Castello J, Ragnauth A, Friedman E, Rebholz H. CK2-An Emerging Target for Neurological and Psychiatric Disorders. Pharmaceuticals (Basel). 2017 Jan 5;10(1). doi: 10.3390/ph10010007. Review. PubMed PMID: 28067771; PubMed Central PMCID: PMC5374411.
Rebholz H, Zhou M, Nairn AC, Greengard P, Flajolet M. Selective knockout of the casein kinase 2 in d1 medium spiny neurons controls dopaminergic function. Biol Psychiatry. 2013 Jul 15;74(2):113-21. doi: 10.1016/j.biopsych.2012.11.013. Epub 2013 Jan 3. PubMed PMID: 23290496; PubMed Central PMCID: PMC3878430.