A Role for P11 in the Therapeutic Responses to Rapid-Acting Antidepressants
Abstract
Depression is one of the most prominent psychiatric symptoms in Parkinson s disease (PD), affecting 30% to 50% of the patients, and causes additional impairment in daily activities in PD patients. In the United States, depression is a common psychiatric disease with an estimated lifetime incidence of over 12% in men and over 20% in women, accounting for a high socioeconomic burden as well as for a major loss of quality-adjusted life year. Currently, the antidepressant drugs called SSRIs (selective serotonin reuptake inhibitors), which mainly increase the availability of the brain chemicals serotonin and norepinephrine, present significant limitations: (1) only half of patients are responding (improved symptoms) to the currently available treatment and (2) it takes a long time (few weeks to several months) to observe the beneficial effect of the treatment. Thus, there is a great need for the development of next-generation treatments with rapid onset of action and higher efficacy for patients resistant to SSRIs. Recently, another type of chemical called glutamate has been shown to be better suited for a rapid therapeutic response, representing an alternative strategy for the treatment of depression. Two essential components responsible for glutamate regulation are cellular receptors called NMDA and mGluR5 receptors. Although much effort has been made, little is known about the molecular and cellular mechanisms of the actions of these antidepressant drugs (e.g., ketamine and MTEP) targeting these receptors. Our laboratory has identified a component, p11, as an important factor mediating depression-like states and antidepressant responses of SSRIs. Our team has recently demonstrated that not all nerve cells are involved in SSRIs effects and identified specific nerve cell types responsible for the therapeutic effect. In preliminary studies, we have also linked p11 to the therapeutic responses to compounds acting on NMDA and mGgluR5 receptors. To uncover novel metabolic pathways involved for depression, we propose to study the relationship between p11 cell type specificity and the beneficial action of ketamine and MTEP in mice. To do this, we will (1) genetically modify mice to specifically remove p11 in the cell types previously identified (critical for the antidepressant actions); (2) determine which cell types are involved in the action of the compounds acting on NMDA and mGluR5 receptors; and (3) look for the common p11-dependent regulators responsible for these responses. With this knowledge, we will be able to provide cellular and molecular framework of p11 in the therapeutic actions of all three classes of antidepressant drugs. Altogether, this work will help us identify novel molecular mechanisms and propose novel therapeutic strategies for the treatment of depression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610681
Entities
People
- Paul Greengard
Organizations
- The Rockefeller University
- United States Army