ABSTRACT
Receptor-interacting protein (RIP140) is a transcription co-regulator highly expressed in macrophages to regulate inflammatory and metabolic processes. However, its implication in neurological, cognitive and emotional conditions, and the cellular systems relevant to its biological activity within the central nervous system are currently less clear. A transgenic mouse line with macrophage-specific knockdown of RIP140 was generated (MΦRIPKD mice) and brain-region specific RIP140 knockdown efficiency evaluated. Mice were subjected to a battery of tests, designed to evaluate multiple behavioral domains at naïve or following site-specific RIP140 re-expression. Gene expression analysis assessed TNF-α, IL-1ß, TGF-1ß, IL1-RA and neuropeptide Y (NPY) expression, and in vitro studies examined the effects of macrophage's RIP140 on astrocytes' NPY production. We found that RIP140 expression was dramatically reduced in macrophages within the ventromedial hypothalamus (VMH) and the cingulate cortex of MΦRIPKD mice. These animals exhibited increased anxiety- and depressive-like behaviors. VMH-targeted RIP140 re-expression in MΦRIPKD mice reversed its depressive- but not its anxiety-like phenotype. Analysis of specific neurochemical changes revealed reduced astrocytic-NPY expression within the hypothalamus of MΦRIPKD mice, and in vitro analysis confirmed that conditioned medium of RIP140-silnenced macrophage culture could no longer stimulate NPY production from astrocytes. The current study revealed an emotional regulatory function of macrophage-derived RIP140 in the VMH, and secondary dysregulation of NPY within hypothalamic astrocyte population, which might be associated with the observed behavioral phenotype of MΦRIPKD mice. This study highlights RIP140 as a novel target for the development of potential therapeutic and intervention strategies for emotional regulation disorders.
Subject(s)
Anxiety/metabolism , Depression/metabolism , Macrophages/metabolism , Nuclear Receptor Co-Repressor 1/metabolism , Ventromedial Hypothalamic Nucleus/metabolism , Animals , Astrocytes/metabolism , Brain/metabolism , Cytokines/metabolism , Emotions/physiology , Gene Knockdown Techniques , Male , Mice , Neuropeptide Y/metabolism , Nuclear Receptor Co-Repressor 1/genetics , Phenotype , RNA, Messenger/metabolismABSTRACT
Lithium, the prototypic mood stabilizer, was recently demonstrated to enhance autophagy in cells. Recent hypotheses regarding the source of therapeutic effects of lithium as well as other mood stabilizers and antidepressants suggest that they may stem from increased neuroprotection, cellular plasticity and resilience. Hence it is clearly a possibility that enhanced autophagy may be involved in the therapeutic action by contributing to increased cellular resilience. A well-documented mechanism to induce autophagy is by inhibition of mTOR, a negative modulator of autophagy and rapamycin (sirolimus) is a commonly used inhibitor of mTOR. Accordingly, the present study was designed to evaluate the effects of rapamycin in animal models of antidepressant activity. A dose-response experiment in the mice forced swim test was performed and followed by additional testing of mice and rats in an open field, the forced swim test and the tail suspension test. Results show that sub-chronic, but not acute, administration of rapamycin doses of 10mg/kg and above, have an antidepressant-like effect in both mice and rats and in both the forced swim and the tail suspension tests with no effects on the amount or distribution of activity in the open field. Whereas it is tempting to conclude that the antidepressant-like effects are related to mTOR inhibition, they may also be the consequences of interactions with other intracellular pathways. Additional studies are now planned to further explore the behavioral range of rapamycin's effects as well as the biological mechanisms underlying these effects.
