Abraham Kovoor, Ph.D. - US grants

Abnormal Movements; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; Applications Grants; Brain; CRISP; Chronic; Computer Retrieval of Information on Scientific Projects Database; Corpus Striatum; Corpus striatum structure; Development; Drug Therapy; Dysfunction; Dyskinesia Syndromes; Dyskinesias; Dyskinetic syndrome; ES Cell Line; ES cell; Embryo; Embryonic; Embryonic Stem Cell Line; Encephalon; Encephalons; Functional disorder; Funding; Grant; Grant Proposals; Grants, Applications; Idiopathic Parkinson Disease; Implant; Institution; Investigators; Knockout Mice; Lewy Body Parkinson Disease; Major Tranquilizers; Mammals, Mice; Mental disorders; Mental health disorders; Mice; Mice, Knock-out; Mice, Knockout; Mother Cells; Movement Disorder Syndromes; Movement Disorders; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; Neuronal Differentiation; Null Mouse; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's disease; Parkinsons disease; Pharmacotherapy; Physiopathology; Primary Parkinsonism; Progenitor Cells; Psychiatric Disease; Psychiatric Disorder; Research; Research Personnel; Research Resources; Researchers; Resources; Rhode Island; Schizophrenia; Schizophrenic Disorders; Source; Stem cells; Striate Body; Striatum; Tardive Dyskinesia; Testing; Toxic effect; Toxicities; Tranquilizing Agents, Major; United States National Institutes of Health; Universities; Unspecified Mental Disorder; abnormal involuntary movement; dementia praecox; design; designing; embryonic stem cell; implantation; mental illness; pathophysiology; professor; psychological disorder; repair; repaired; schizophrenic; stem cell of embryonic origin; striatal

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have provided data suggesting a role for RGS9-2 in the striatal control of movement and in the movements side-effects of the pharmacotherapy of schizophrenia and Parkinson's disease. For example we showed that RGS9 knockout mice develop abnormal movements that closely resemble drug-induced dyskinesias (DID). DID are unexplained movement side-effects of the pharmacotherapy of Parkinson's disease and schizophrenia, and are thought to result from the chronic actions of the respective drugs on striatal D2-dopamine receptors (D2R). In addition we showed that RGS9-2 targets to D2R and proposed that RGS9-2 either functionally or spatially compartmentalizes D2R in striatal neurons. Thus drug-induced alterations in RGS9-2 mediated striatal D2R cellular compartmentalization may lead to abnormal striatal signal processing and to drug-induced abnormal involuntary movements. Determining how such compartmentalization is altered will require a better understanding of the D2R-RGS9-2 interaction suggested by our previous studies. Thus we will continue with our studies that will test if the targeting RGS9-2 toD2R involves a direct or indirect interaction and map the interacting surfaces. We will also attempt to reconstitute coupling between D2R and ion channels, such as NMDA-receptors that generate and shape striatal signals. We will test if co-expressed RGS9-2 can alter D2R-channel coupling. From a parallel clinical study we have identifed non-synonymous mutations and intronic deletions in the RGS9 gene that are enriched in patients with schizophrenia and Parkinson's disease. Thus we will test the hypothesis that these RGS9 gene variations produce alterations in RGS9-2 cellular functions.