Section: Research

Postdoctoral Position Available

Schahram Akbarian, Ph.D.,M.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Psychiatry

Other Affiliation(s):
   Brudnick Neuropsychiatric Research Institute
   Interdisciplinary Graduate Program
   Program in Neuroscience

The Prefrontal Cortex and Schizophrenia

Schizophrenia is a major psychiatric disorder that involves dysfunction of the prefrontal cortex and other brain regions important for cognition and executive functions. Like many other psychiatric illnesses, the disorder is likely to result from a complex interaction of genetic factors operating in conjunction with a diverse set of other mechanisms. Gaining a better understanding of epigenetic regulators of gene expression and chromatin function in the prefrontal cortex might advance current knowledge on the molecular pathology of the disorder, and shed light on the molecular principles governing the long period of prefrontal maturation, which extends into, or even beyond, the second decade of life.

Our experiments are designed to map histone and DNA modifications in prefrontal chromatin surrounding schizophrenia susceptibility genes, and to explore potential changes related to normal development, or disease, or psychotropic medication.

Dopaminergic Signaling Induces Chromatin-Remodeling in Neurons

Dopaminergic signaling in striatum is involved in neuropsychiatric disease, including drug abuse and psychosis. Stimulants, antipsychotics and other drugs targeting the dopaminergic system regulate transcription in striatal neurons, but the underlying molecular mechanisms are not completely understood. Gaining a better understanding of how dopaminergic drugs induce transcription of early and late response genes should broaden the range and efficacy of treatment strategies for major neuropsychiatric illnesses such as schizophrenia, depression and drug addiction.

Our experiments are designed to examine the dopaminergic regulation of covalent histone modifications in striatum, using acute and chronic paradigms. Histones are, together with DNA that wraps around them, the fundamental structural unit of chromatin and thus regulate gene expression, DNA repair and chromosome segregation, among others. Specifically, a histone code has been established, associating the site-specific acetylation, methylation and phosphorylation of the amino-terminal tails of core histones either to open chromatin and active gene expression or to silence inactive and condensed chromatin.

Our central goals are to examine on a molecular and cellular level dynamic changes in histone acetylation, methylation and phosphorylation after single or repeated administration of stimulant drugs, dopamine receptor agonists and antagonists. Furthermore, we examine the intracellular messenger pathways that couple dopamine receptor signaling to the chromatin-remodeling complex in the nucleus.

Our central hypothesis is that histone modifications defining open and closed chromatin are differentially regulated after stimulation or blockade of dopamine receptors from the D₁ and D₂ class.

Our experiments rely on chromatin immunoprecipitation assays, immunoblotting and laser capture-microdissection of cells labeled with anti-histone antibodies selectively recognizing site-specific modifications at the NH₂-terminal tails of histones H3 and H4. It is expected that these novel approaches will provide a clear picture on the dopaminergic regulation of the “histone code” in striatal neurons and will establish the epigenetic modification of striatal chromatin as a novel mechanism of action for stimulant and antipsychotic drugs.

Mecp2 Mutant Mice – Genetic Model for Rett Disorder

Rett syndrome is an X-linked neurological disease of early childhood mainly affecting females. It is associated with deleterious mutations of the gene encoding methyl-CpG-binding protein 2 (MECP2) but it remains unclear how MECP2-deficiency results in neuronal disease. MECP2 is thought to regulate acetylation, methylation and other post-translational modifications of the core histones, that together with DNA wrapped around them comprise the fundamental structural unit of chromatin and thus regulate gene expression, DNA repair and chromosome segregation.

Our central goals are to test the hypothesis that histone hyperacetylation contributes to the Rett syndrome phenotype. We will monitor in wildtype and genetically engineered, Mecp2-deficient mutant mice developmentally regulated changes in histone H3 and H4 covalent modifications at defined genomic regions. Furthermore, we will treat mutant and control mice with chromatin modifying drugs and monitor the resulting changes in behavior and brain pathology.

Phone: 508-856-2674
E-mail: Schahram.Akbarian@umassmed.edu
Keywords: Genetic Systems, Neurobiology

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Akbarian for additional details.