Aging and Antipsychotic Efficacy - Epigenetic Mechanisms

Summary

Principal Investigator: Hongxin Dong
Abstract: DESCRIPTION (provided by applicant): Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psycho- pathological conditions, including psychosis and behavioral disturbances associated with cognitive impairment. However, the current treatment strategy for elderly individuals is often ineffective, with an increased incidence of sid effects. The factors contributing to reduced antipsychotic efficacy in the elderly population are not yet full understood. Induction of immediate-early genes such as c-fos has been shown to affect antipsychotic drug activity in the CNS. Both typical and atypical antipsychotics induce c Fos expression in specific brain regions, including the striatum and prefrontal cortex. Our preliminary data shows lower levels of antipsychotic induced c-Fos expression in the nucleus accumbens of aged mice, as well decreased acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter. Co-treatment with valproic acid (VPA), a histone deacetylase HDAC inhibitor, was shown to restore antipsychotic induced c-Fos induction and improve behavioral performance in aged mice. Our preliminary data suggests that an epigenetic mechanism may play a key role in the reduced drug efficacy seen in elderly individuals. In this study, we hypothesize that age-associated decreases in antipsychotic efficacy are the result of epigenetic changes in the brain that can be ameliorated by co-treatment with antipsychotics and HDAC inhibitors. To test our hypotheses, young (3-month old) and aged (24-month old) mice will be treated with haloperidol (HAL, a typical) or clozapine (CLZ, an atypical) alone or in combination with the HDAC1-specific inhibitor entinostat (MS-275) or pan-HDAC inhibitor VPA for 14 days. First, we will investigate the relationship between the acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter and antipsychotic induced c-Fos induction in the brains of aged mice using chromatin immunoprecipitation (ChIP) assays and real-time PCR. We will then examine whether increased c-Fos expression following HDAC inhibitor/antipsychotic co-treatment is specific to dopaminergic or serotoninergic neurons using immunofluorescence double labeling. Using behavioral tests relevant to memory and motor function, we will then investigate whether MS-275 treatment results in cognitive improvements similar to those seen with VPA treatment. This study will shed light on the interactions between aging, antipsychotic drug efficacy, and epigenetic regulation. By advancing our understanding of the epigenetic mechanisms of drug efficacy, it will be possible to develop new psychotropic treatment strategies that maximize benefits while minimizing side effects.
Funding Period: 2012-12-26 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation
    Janitza L Montalvo-Ortiz
    Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
    Neuropsychopharmacology 39:1469-78. 2014
  2. ncbi Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice
    Hongxin Dong
    Department of Psychiatry and Behavioral Sciences, Feinberg School Medicine, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA
    Psychopharmacology (Berl) 231:4711-22. 2014

Detail Information

Publications2

  1. pmc HDAC inhibitors restore the capacity of aged mice to respond to haloperidol through modulation of histone acetylation
    Janitza L Montalvo-Ortiz
    Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
    Neuropsychopharmacology 39:1469-78. 2014
    ....
  2. ncbi Effects of corticotrophin-releasing factor receptor 1 antagonists on amyloid-β and behavior in Tg2576 mice
    Hongxin Dong
    Department of Psychiatry and Behavioral Sciences, Feinberg School Medicine, Northwestern University, 303 E Chicago Ave, Chicago, IL, 60611, USA
    Psychopharmacology (Berl) 231:4711-22. 2014
    ..However, whether CRF receptor 1 (CRF1) antagonists could influence the stress-induced acceleration of an AD-like process in mouse models has not been well studied...

Research Grants30

  1. Control of Latent/Persistent HIV Infection in Primary CD4 T Cells
    Celsa A Spina; Fiscal Year: 2013
    ..Knowledge derived from these studies will add significantly to our understanding of the molecular mechanisms controlling HIV latency --- which is a critical step in the path to developing new treatment strategies. ..
  2. Neurotensin-1 Receptor as a Therapeutic Target for Schizophrenia
    David Feifel; Fiscal Year: 2013
    ..The proposed experiments may help lead to completely novel and superior treatments for schizophrenia. ..
  3. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  4. Epigenetic Regulation of Hippocampal Synaptic Plasticity
    MORGAN STUART BRIDI; Fiscal Year: 2013
    ..I propose here to investigate in parallel the roles of Sin3a and the Nr4a transcription factors in hippocampal synaptic plasticity, and to uncover the identity of their regulatory targets in the hippocampal genome. ..
  5. Amphetamine-Induced Transcriptional Plasticity in Striatal GABAergic Interneurons
    ANNE ELIZABETH WEST; Fiscal Year: 2013
    ..abstract_text> ..
  6. HIV Latency, Epigenetics, and Therapeutics
    David M Margolis; Fiscal Year: 2013
    ..Therefore a more detailed understanding is needed of the epigenetic mechanisms behind persistent infection. ..
  7. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  8. Epigenetics underlies long-term risk of relapse during abstinence
    Kristine M Wiren; Fiscal Year: 2013
    ....
  9. Remodeling Neuronal Chromatin in Mouse Models for Depression
    Schahram Akbarian; Fiscal Year: 2013
    ..Then, indirectly, the chromatin changes brought about by Setdb1 result in certain adaptations in the communication between nerve cells, ultimately resulting in an antidepressant-like effect. ..
  10. EINSTEIN AGING STUDY
    Richard B Lipton; Fiscal Year: 2013
    ..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
  11. Neuroprotective immunity and HIV dementia
    Howard E Gendelman; Fiscal Year: 2013
    ..An interdisciplinary team of investigators with a strong track record of working together successfully was assembled for these studies. ..
  12. Endogenous Kynurenic Acid Modulates Prefrontal ACh Levels and Cognitive Behavior
    Robert Schwarcz; Fiscal Year: 2013
    ..We will use these findings to generate an experimental platform for testing the therapeutic efficacy of KYNA-based treatments in alleviating the cognitive deficits seen in SZ. ..