The objective of this study is to validate the RGS9 knockout mouse as an animal model for tardive dyskinesia (TD). Antipsychotic drugs have revolutionized the treatment of schizophrenia, but an unfortunate side-effect is the development of TD, a debilitating hyperkinetic movement disorder. The liability of """"""""typical"""""""" first-generation antipsychotic drugs to produce TD was recognized more than 50 years ago. Yet, very little of the underlying pathophysiology is understood other than that a necessary factor is the chronic blockade of D2- like dopamine receptors (D2R) expressed in the striatum. While the second-generation """"""""atypical"""""""" drugs have a significantly reduced risk for producing TD, recently published results from clinical studies such as CATIE have emphasized their association with fatal cardiovascular and metabolic disorders and suggest a renewed role for the typical drugs in the pharmacotherapy of schizophrenia. However, the renewed use of the typical drugs depends critically on better understanding, managing and treating their potentially irreversible and serious side- effect, TD. A major impediment for understanding, managing and treating TD has been the lack of a practical animal model: the vacuous chewing rodent model and the more analogous primate model are extremely inefficient and expensive-large numbers of animals are treated for months to years to produce enough animals with TD-like symptoms. Thus the development of a useful, reliable and inexpensive mouse model of TD will be an important contribution to improving schizophrenia pharmacotherapy. The rationale for this study lies in data recently published by this principal investigator and others which suggest that a brain RGS protein, RGS9-2, is critical in the development of TD. They include the following observations: 1) RGS9-2 is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement and the brain structure that is critical in TD etiology, 2) RGS9-2 specifically colocalizes with D2R, the major target of antipsychotic drugs and specifically modulates D2R-activated striatal signaling pathways and 3) RGS9-2 knock-out mice developed hyperkinetic abnormal involuntary movements (AIMs) resembling TD after only three days of treatment with haloperidol, a typical antipsychotic drug. Here we propose to test the hypothesis that the RGS9 knockout mouse has etiological validity and models the clinical condition. An important etiological feature of TD is that it is produced by drugs that block D2R with high affinity (e.g. older typical antipsychotics), and lower affinity blockers (e.g. second generation antipsychotics) produce a lower incidence of TD. In addition once TD develops it is not easily reversed by cessation of drug-treatment. We will determine if these key clinical features of TD are preserved in the knockout mouse model. We will also test if exogenous viral-mediated striatal expression of RGS9-2 in the mouse model can suppress antipsychotic- induced AIMs. Such an experiment will help to confirm that altering RGS9-2 levels in adult striatum of the mouse model alters susceptibility to antipsychotic-induced AIMs and point to a strategy for treating TD.
A major debilitating and irreversible side-effect that limits the usefulness of drugs used to treat schizophrenia is the development of involuntary movements called tardive dyskinesia (TD). Very little is known about how TD occurs and how to treat it because of the lack of a convenient animal model. This application describes the development and validation of a mouse strain that lacks a functional gene for a protein called, RGS9-2, as a novel and convenient animal model for studying and learning to treat TD.
| Octeau, J Christopher; Schrader, Joseph M; Masuho, Ikuo et al. (2014) G protein beta 5 is targeted to D2-dopamine receptor-containing biochemical compartments and blocks dopamine-dependent receptor internalization. PLoS One 9:e105791 |
| Celver, Jeremy; Sharma, Meenakshi; Thanawala, Vaidehi et al. (2013) Arrestin-dependent but G-protein coupled receptor kinase-independent uncoupling of D2-dopamine receptors. J Neurochem 127:57-65 |
| Sharma, Meenakshi; Celver, Jeremy; Octeau, J Christopher et al. (2013) Plasma membrane compartmentalization of D2 dopamine receptors. J Biol Chem 288:12554-68 |
| Sharma, Meenakshi; Celver, Jeremy; Kovoor, Abraham (2011) Regulator of G protein signaling 9-2 (RGS9-2) mRNA is up regulated during neuronal differentiation of mouse embryonic stem cells. Neurosci Lett 502:123-8 |
