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.

Figure

A model whereby cAMP and NMDA receptor pathways modify chromatin in striatal neurons in response to blockade of D₂- or activation of D₁-like signaling. Blockade of D₂-like receptors removes the D₂-mediated inhibition of adenylyl cyclase (AC) activity through G_I subunits. Likewise, activation of D₁ receptors activates AC through G_o and other subunits. As a result, cAMP levels increase, thereby activating cAMP-dependent PKA (cAMP-PKA). Increased cAMP-PKA activity may then phospho-activate the NR1 subunit of the NMDA receptor, thereby activating NMDA receptor-regulated Ca²⁺ -dependent signaling pathways including L-type voltage sensitive Ca²⁺ channels (LVSCC) and Ca²⁺/calmodulin dependent kinases (CAMKs). Activation of LVSCC after inhibition of D₂-like signaling may involve additional cellular messengers other than cAMP-PKA. Furthermore, glutamatergic input from the cerebral cortex and other brain regions may activate postsynaptic NMDA receptors and LVSCC in striatal neurons. It is yet unclear which histone modifying enzymes are regulated by the cAMP-PKA and NMDA receptor and Ca²⁺-dependent pathways. However, both CAMKs and PKA have been shown to phosphorylate histone H3 and both types of kinases are known to phospho-activate CREB. Phospho-activated CREB may recruit histone acetyl-transferases, including CREB binding protein (CBP)  that in concert with other enzymes then could phospho-acetylate H3 at serine 10 and lysine 14.

Representative Publications

Schroeder FA, Pental KL, Matevossian A., Jones SR, Konradi C, Tapper AR, Akbarian S (2008) Drug-induced activation of dopamine D₁ receptor signaling and inhibition of class I/II histone deacetylase induces chromatin remodeling in reward circuitry and modulates cocaine-related behaviors. Neuropsychopharmacology 33:2981-2992.

Jiang Y, Matevossian A, Huang HS, Straubhaar J, Akbarian S (2008) Isolation of neuronal chromatin from brain tissue. BMC Neuroscience 9:42.

Mellios N, Huang HS, Grigorenko A, Rogaev E, Akbarian S (2008) A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Human Molecular Genetics 17: 3030-3042.

Jiang Y., Langley B., Lubin F.D., Renthal W., Wood M.A., Yasui D.H., Kumar A., Nestler E.J., Akbarian S., Beckel-Mitchener A.C. (2008) Epigenetics in the nervous system. Journal of Neuroscience 28: 11753-11759.

Mellios  N, Huang HS, Galdzicka M, Ginns E, Akbarian S (2009) Molecular determinants of dysregulated GABAergic gene expression in schizophrenia. Biological Psychiatry 65: 1006-1014.

Akbarian S (2008) Restoring neuronal synchrony in schizophrenia. American  J Psychiatry 165:1507-1509.

Matevossian A., Akbarian S. (2008) A chromatin assay for human brain tissue. Journal of Visualized Experiments 13: pii: 7171. doi: 10.3791/717.

Connor, CM, Akbarian S (2008) DNA methylation changes in schizophrenia and bipolar disorder. Epigenetics 3(2): 55-58.

Akbarian S (2008) Approaching the molecular pathology of suicide. Biological Psychiatry 64: 643-644.

Akbarian S, Huang HS (2008) Epigenetic regulation in human brain – focus on histone lysine methylation. Biological Psychiatry 65: 198-203.

Matevossian A., Akbarian S. (2008) Neuronal nuclei isolation from human postmortem brain tissue. Journal of Visualized Experiments 20: pii:914. Doi:10.3791/914.

Connor CM, Guo Y, Akbarian S (2009) Cingulate white matter neurons in bipolar disorder and schizophrenia. Biological Psychiatry 2009 Sep 1;66(5):486-93. Epub 2009 Jun 25.

Febo M, Akbarian S, Schroeder FA, Ferris CF. (2009) Cocaine-induced metabolic activation in cortico-limbic circuitry is increased after exposure to the histone deacetylase inhibitor, sodium butyrate. Neurosci Lett. 465:267-271.

Akbarian S (2009) The molecular pathology of schizophrenia-Focus on histone and DNA modifications. Brain Res Bull [Epub ahead of print].

Potential Rotation Projects

1. Drug-induced adaptations in neuronal circuitry contributing to psychosis or addiction could be viewed as a form of neuronal plasticity and thus may depend on similar molecular mechanisms that operate in learning and memory centers of the brain. The goal of this project is treat mice with chromatin modifying drugs and to explore the resulting molecular adaptations in nuclei of neurons located in fore- and hindbrain.  Students will gain experience in mouse genetics, neuroanatomy and various chromatin assays. Furthermore, students will have the opportunity to study current models of major psychiatric disease, including schizophrenia, mood disorders and addiction.

2. The genome of vertebrates is subject to epigenetic modifications, including the methylation of cytosine residues in symmetrically positioned CpG dinucleotides. DNA-methylation has profound effects on transcriptional activity and chromosomal stability. The goal of this project is to determine the regulation of DNA-methylation in developing and aging brain. Students will apply various techniques to examine DNA-methylation patterns of selected gene sequences in defined cell populations of the CNS.
   

Academic Background

Clinical Assistant in Psychiatry
Massachusetts General Hospital and McLean Hospital
Harvard Medical School
Belmont, MA

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.